static-content.springer.com10.1007/s00… · Web viewGene/variant/ID. Novelty. Clinical Synopsis On...

Supplementary Table S2

Gene/variant/ID Novelty Clinical Synopsis On Families Harboring Novel Candidate Genes

ANKHD1 NM_017747.2:c.7365dup:p.(His2456Serfs*13) (17DG0763)

Novel candidate gene/this study

A 3 years old girl with failure to thrive, short stature, microcephaly, speech delay, anteriorly placed anus and dysmorphic features. She was born preterm with IUGR to consanguineous parents.

ASTN2 NM_014010.4:c.892G>C:p.(Asp298His) (15DG0307)


A 1 year old boy with dysmorphic features who was born at full term via NSVD to G7P4+2 35 years old mother with normal growth parameters. Pregnancy was complicated by low lying placenta necessitating admission for two weeks towards the day of delivery. He was found to have hypospadias with chordee that led to recurrent UTIs. He sat unsupported at 8 months, but he still cannot stand or bear weight. He can only say dada, and he has stranger and separation anxiety. His parents are consanguineous with a family history of cleft lip and intellectual disability. His examination was significant for a flat nose, frontal bossing, abnormal frontal and side hairlines, anteverted nares and a café au lait spot on the inner thigh. His growth parameters at 1 year of age were weight 10.1 kg (25th-50th percentile), height 75 cm (25th-50th percentile) and head circumference 46 cm (25th-50th percentile).

ATP13A1 NM_020410.2:c.1045G>A:p.(Glu349Lys) (13DG1545)


Patient 1 and 2 are two sisters 6 and 7 years old, respectively, with developmental delay, ADHD, and recurrent respiratory infections since age 6 months. Both of them have language delay and intellectual disability as well as higher cerebral function deficit. They are the product of consanguineous marriage with no history of abortion or neonatal death; however, there is a positive family history of a similar condition. They share similar facial features with down slanting eyes, low hairline, prominent nose, and mild hyperplasia of the maxilla. They also noted to have flattened nails, otherwise normal dermatological examination. All other examinations were within normal limits. Growth parameters for patient 1 at 6 years of age were weight 19.4 kg (75th percentile), height 102 cm (10th-25th percentile) and head circumference 48 cm (10th -25th percentile). Growth parameters for patient 2 at 7 years of age were weight 14.3 kg (25th percentile), height 104 cm (10th percentile) and head circumference 49 cm (10th percentile).

FMO4 NM_002022.1:c.83C>A:p.(Pro28His) (13DG1202)


An 11 years old boy who was born via NSVD to G2P1+0 23 years old mother following an uneventful pregnancy. He required oxygen for less than one hour, but he was not admitted to NICU and was discharged on the second day. The first concern was at 5 months of age due to cyanotic episode and floppiness, and he was investigated by a brain MRI and found to have abnormal myelination. He also has peripheral nerve involvement confirmed by nerve conduction studies and biopsy that showed a progressive axonal loss. He gradually started to have deformities in his feet, hands and back. He sat at 18


months and walked with a walker at 4 years of age; however, he lost the ability to walk later on. He responds to his mother’s verbal commands. His estimated IQ was 65. He seems to have a borderline progressive microcephaly. He is drooling and wheelchair bound. His parents are first-degree consanguineous couple once removed with another affected son and two other healthy children, and there are no other affected members. His physical examination was significant for drooling, scoliosis, bilateral claw hands, bilateral drop feet and areflexia. Other examinations were within normal limits. His growth parameters at 11 years of age were weight 19 kg (<1st percentile, -3.35 SD) and head circumference 50 cm (on the 1st percentile).

H2BFM NM_001164416.1:c.124C>T:p.(Arg42*) (17DG0782)


A 3.5 years old boy with autism spectrum disorder and speech delay. Developmentally, he walked at the age 13 months, can run and walk upstairs but not downstairs. He can finger feed and scribble with pencil. He says mama and baba (non-specific), and understands simple commands. He was born at term by vaginal delivery with vacuum assistance, birth weight was 3.88kg. He prefers to play alone. Parents are healthy and not consanguineous.

MADD NM_003682.3:c.593G>A:p.(Arg198His) / NM_003682.3:c.979C>T:p.(Arg327*) (17DG0770)


A 6 years old girl with a speech delay and autism. She was born at 38 3/7 weeks gestation via a C-section as part of a twin gestation secondary to IVF to a 34 years old G3P2 mother. Pregnancy was uncomplicated, and Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. There were no teratogens exposure, and maternal medications during pregnancy were low-dose aspirin and progesterone in early pregnancy. She was hospitalized for 3 days after birth, and her growth parameters at 7 days of age were weight 2.6 kg (on the 8th percentile), length 47 cm (on the 4th percentile) and head circumference 34.1 cm (on the 36th percentile). Early development and milestones were normal until 15 months of age when speech began to be delayed compared to her twin brother, and she had difficulty with social interactions and poor eye contact. She was subsequently diagnosed with autism spectrum disorder and was started on ABA therapy. At 3 years of age, she had only 25-50 words vocabulary. She also has some difficulty with sleep, waking up every 2-3 days for prolonged periods at night. She had some tantrums, particularly with routine change and will not play cooperatively with other children, though she will play independently alongside them. Her parents are a nonconsanguineous couple, and her mother had a speech delay as a child. Her twin brother is also mildly delayed compared to his peers. She has two half cousins with ADHD, dyslexia and learning difficulties. Her growth parameters at 3 years and 7 months of age were weight 15.6 kg (50th-75th percentile) and height 99.1 cm (50th-75th percentile), and her head circumference at 16 months of age was 47.5 cm (75th-90th percentile).

MADD NM_003682.3:

Novel candidate

A 14 months deceased girl who was born at 42 weeks gestational age via NSVD to a 32 years old mother following a pregnancy that was complicated by decreased fetal movements. After birth, she was found to


c.2930T>G: p.(Leu977Arg)p.(Val977Gly) (17DG0771)

gene/this study

have meconium stained amniotic fluid and respiratory distress that needed CPAP for 24 hours. The Apgar scores were 5, 6, 8 at the 1st, 5th, and 10th minutes, respectively, and her growth parameters at birth were weight 3.15 kg (25th-50th percentile), height 49 cm (25th-50th percentile) and head circumference 35 cm (on the 75th percentile). She developed persistent hypoglycemia since the first day of life that needed D10 and then D15. On the 20th day of life, she developed seizures despite optimal glycemic control. Developmentally, she has a profound developmental delay. Her parents are consanguineous with 4 other healthy children, and there is no family history of a similar condition. Her examination was significant for downslanting palpebral fissures, depressed nasal bridge, posteriorly rotated ears, long philtrum, small mouth, head lag, micrognathia, short neck, widely spaced nipples, overriding of the 4th toe on the left foot, varus deformity and poor visual contact. Her growth parameters at 14 months of age were weight 6 kg (<3rd percentile), height 65 cm (<3rd percentile) and head circumference 39 cm (<3rd percentile). Skeletal survey, abdominal US, CGH, newborn screen, urine organic acid, VLCFA, plasma amino acids, NH3 and lactic acids were all within normal limits. Brain MRI at 5 months of age showed delayed myelination and bilateral globus pallidus T2 hyperintensity.

MFSD11 NM_001242532.1:c.143G>C:p.(Gly48Ala) (15DG2492)


A 6 years old boy with intellectual disability, genitourinary anomalies, cardiac defects, short stature and non-specific elevations in several plasma amino acids and urine orotic acid.

NCKAP1 NM_205842.2:c.3298G>T:p.(Glu1100*) (12DG1370)


A 6 years old girl who was born via NSVD to a healthy 20 years old primigravida following a pregnancy that was complicated by threatened abortion. The antenatal and perinatal histories were unremarkable, and she was discharged on the second day. The first abnormality was noted at 14 months of age when she had tip-toeing and extensive investigations at that time were normal. She had two seizures at 26 and 28 months of age, and she has been seizure-free since then. She is now off medications. However, the primary concern was noted at the age of three years when she had an expressive language delay. Her cognitive abilities, in general, were reduced. She was evaluated by a psychiatrist and was diagnosed with ADHD and was started on medications. She also had an estimated IQ of 76. Her mother also noticed that she has frequent sleep panic attacks. Her parents are nonconsanguineous with another mildly affected daughter. Her father also has mild cognitive impairment, and there are multiple family members affected on the paternal side. Physical examination revealed mild hypertelorism and hypopigmentation on the back, and other examinations were within normal limits. Her growth parameters at 9 years of age were weight 44.2 kg ( >97th percentile), height 150 cm (>97th percentile, +2.64 SD) and head circumference 55.5 cm (>99th percentile, + 2.68 SD). EEG, brain MRI, CBC, tandem mass spectrometry and CGH


microarray were within normal limits.

NFASC NM_001160331.1:c.1109G>C:p.(Arg370Pro) (14DG0056)


A 3 months old girl who presented during neonatal period with congenital stridor and generalized hypertonia. Her birth weight was 3.2 kg, and she showed poor weight gain since birth even though she was on NG-tube feeding. Developmentally, she has a global developmental delay affecting all domains. She shows no purposeful movements and has a prolonged grasp reflex. She does not have a social smile, but she can babble and coo. There is a family history of a similar condition in two siblings; a brother who died at the age of 3 months and an older sister who is currently 21 months with GDD and Hypertonia. There is also a paternal cousin with similar presentation. On examination, she has a nonexpressive face with subtle dysmorphism and mild positional deformity of the chest wall. Her current growth parameters at 3 months of age were weight 3.2 kg, length 53 cm and head circumference 36.5 cm; all are below the third percentile. On neurological examination, there is a generalized hypertonia affecting upper limbs more than lower limbs and hyperreflexia without a clonus. Hearing and vision were intact, and other examinations were within normal limits.

A 3 years old boy who was born at 34 weeks gestation via an emergency C-Section due to fetal distress. His Apgar scores were 4 and 7 at 1 and 5 minutes, respectively. He has a respiratory difficulty at birth, and he was subsequently intubated and admitted to NICU. His growth parameters at birth were weight 2.1 kg and head circumference 33.5 cm, and he was noted to have a very small anterior fontanel at birth. He stayed in NICU for 9 months. A tracheostomy was placed for him because he failed extubation several times. He had frequent hospital admissions due to pneumonia and sepsis. There is a positive family history of a similar condition in a male sibling who died due to the same condition and in two cousins. His physical examination was significant for hypertelorism, high and wide nasal bridge, micrognathia, glossoptosis, cleft palate, long thin and hyperextensible fingers and hypotonia. Other examinations were within normal limits. Brain MRI showed diffuse white matter T2 hyperintensity. Skeletal survey showed 11 pairs of ribs. EMG, Nerve conduction, echocardiography, karyotyping, CGH microarray, CK assay, neonatal screen, and urine organic acids were within normal limits.

The other affected family member had hypertelorism, micrognathia, very small anterior fontanel and hyperextended fingers. The other affected family member had had respiratory distress after birth, and required prolonged NICU admission with several failed extubations.

PCDHGA10 NM_032090.1:c.823G>A:p.

Novel candidate gene/this

A 6 years old boy with GDD, dysmorphic features, bicuspid aortic valve, a cleft lip and inguinal hernia. He was born at full term via NSVD to a G5P4+0 31 years old mother following an uneventful pregnancy. His growth parameters at birth were weight 2.55 kg (on the 5th percentile), length 47 cm (on the 10th


(Glu275Lys) (14DG1188) study

percentile) and head circumference 30 cm (<3rd percentile). A cleft lip was apparent since birth, and it was repaired later on. He also was found to have an inguinal hernia that was repaired, and he also has recurrent otitis media infections from an early age. Developmentally, he had a global developmental delay. He walked at the age of 19 months, and he had a delayed speech. His estimated IQ was 70-75. His parents are first-degree cousins, and there is no family history of a similar condition. However, there is a family history of Klippel-Feil syndrome and learning disability in an uncle and a cousin, respectively. His examination was significant for microcephaly, brachycephaly, anteverted ears, bulbous nasal tip, long philtrum, thin upper lip, downturned corners of the mouth, mild synophrys and flat feet. Other examinations were within normal limits. His current growth parameters at 6 years of age were weight 19.7 kg (50th percentile), height 113 cm (50th percentile) and head circumference 45 (<3rd percentile). CT of the head revealed quadrigeminal cistern arachnoid cyst. Cardiac echocardiogram showed bicuspid aortic valve.

PCDHGA10NM_032090.1:c.2477dupA:p.(Ile827Aspfs*6) (DD_91704)


A 30 months old boy with global developmental delay, congenital microcephaly, infantile spasms and mild dysmorphic features. He was born at full term via NSVD to a healthy mother following an uneventful pregnancy. His growth parameters at birth were weight (on the 25th percentile), height (on the 25th percentile) and head circumference 31 cm (on the 3rd percentile). At the age of 9 months, he developed seizures consisting of several daily episodes of typical infantile spasms with sudden flexion and a tonic fashion of the body, arms and legs. His infantile spasms were refractory to ACTH, but it improved with valproic acid and levetiracetam. Developmentally, he has a global developmental delay affecting all domains. At the age of 8 months, he was unable to sit and control his head. He currently cannot walk, and his speech is severely delayed. His parents are a second-degree consanguineous couple, and he is their only child. Physical examination revealed anteverted ears, thin upper lip vermilion, brisk tendon reflexes, absent visual following and dystonic posturing that is more prominent on the left side. The hearing was normal, and other examinations were within normal limits. His head circumference at the age of 26 months was 42 cm (<3rd percentile).

PPP1R21 NM_001135629.2:c.2089C>T:p.(Arg697*) (17DG0773)


A 28 months old girl who was born at 37 weeks of gestation via C-section due to breech presentation. An antenatal scan showed mild bilateral ventriculomegaly; otherwise, the prenatal course was uncomplicated. Growth parameters at birth were weight 3.25 kg, length 52 cm and head circumference 36 cm, and Apgar scores were 8, 9, and 9, at 1, 5, and 10 minutes, respectively. After birth, she was admitted to NICU due to respiratory distress for one week, and a head sonogram during that admission showed a mild dilatation of the lateral and third ventricles and an echocardiogram at the 4th day showed small PDA, small PFO, and mild septal hypertrophy. She was also noted to have hypotonia, weak sucking and dysmorphic facial


features. She was re-hospitalized at the age of 2 weeks when she developed respiratory distress due to aspiration, and NG-tube feeding was initiated. Repeated echocardiogram at the age of 4 weeks was normal. She had frequent respiratory infections with multiple hospital admissions, and her respiratory status continued to decline until she became dependant on a mechanical ventilator through a tracheostomy. A gastrostomy tube was placed for feeding. Her parents are consanguineous with a history of maternal abortion at 8 weeks of gestation in a previous marriage. She has a significant hypotonia, weakness and decreased movement of limbs from birth. She can only move her extremities with gravity. Developmentally, she has a severe global developmental delay affecting all domains. She does not show any purposeful movement, and she cannot speak or make any sounds. She can only regard faces and smile. Her physical examination revealed a broad nasal bridge, upward slanted palpebral fissures, coarse facial features, generalized hirsutism, low-set posteriorly rotated ears, thick lower lip, high arched palate, hepatomegaly and bilateral myopia. Her neurological examination showed roving eye movements, rotatory nystagmus, generalized hypotonia, areflexia and weakness (minimal movements in upper limbs against gravity and no spontaneous movements noted in lower limbs). Other examinations were within normal limits. Her growth parameters at 28 months of age were weight 11.3 kg (10-25th percentile), length 86 cm (10-25th percentile) and head circumference 48 cm (50-75th percentile). Brain MRI showed a reduced brain volume with prominent CSF spaces, cerebellar vermis hypoplasia with absent inferior vermis, thin corpus callosum, delayed myelination, cavum septum pellucidum and mega cisterna magna. Muscle biopsy was normal. Abdominal sonography showed increased echogenicity of the liver and hepatomegaly. EEG showed diffuse fast beta activity in both hemispheres, predominantly in the posterior regions, occasionally superimposed over slow delta activity. Liver function test, thyroid function test, CPK, ammonia, lactate, plasma amino acids, urine organic acids, acylcarnitine profile, VLCFA, karyotyping and chromosomal microarray analysis were normal. Screening for lysosomal, peroxisomal and storage disorders was also normal. Lysosomal enzymes in cultured skin fibroblasts (beta-galactosidase, total beta-hexosaminidase, beta-hexosaminidase A, arylsulphatase A, beta-glucuronidase, alpha-mannosidase, alpha-fucosidase, palmitoyl-protein thioesterase 1, tripeptidyl peptidase I, sphingomyelinase, Alpha-NAc-galactosaminidase, beta-glucocerebrosidase, beta-galactocerebrosidase, and acid lipase) were all within normal limits.

SLC12A2 NM_001046.2:c.2617-2A>G (17DG0776)


A 3 years old boy with global developmental delay, failure to thrive, hypotonia and microcephaly. He was born at 35 weeks gestation via NSVD following an uneventful pregnancy. He was admitted to NICU for one month due to respiratory distress. He has severe GDD in all domains, and his developmental age is 10 months at 3 years of chronological age. He can sit without support, but he cannot walk or stand. He can only say mama and dada. He is feeding through NG-tube due to recurrent aspirations. His parents are a


first-degree consanguineous couple with four healthy children, another affected daughter and deceased child at 8 years of age with developmental delay and a seizure disorder, and there is no family history of a similar condition in other members. His examination was significant for microcephaly, scaphocephaly and axial hypotonia. Other examinations were within normal limits. His growth parameters at 3 years of age were below the 3rd percentile. Brain MRI and spectroscopy were within normal limits. Skeletal survey revealed osteopenia with questionable radioulnar metaphyseal changes. Tandem MS, urine organic acid, lactate, ammonia, plasma amino acids, CPK and VLCFA were within normal limits. Plasma homocysteine and uric acid were low. Chromosomal microarray showed duplication in 1P12-P11.2 of unknown significance.

SLK NM_014720.1:c.1414G>T:p.(Glu472*)(17DG0777)


A 9 years old girl with early-onset global developmental delay, poor feeding and recurrent chest infections. She was born at full term via an assisted vaginal delivery. After birth, she was admitted to the nursery for 3 days due to transient neonatal jaundice. Later in infancy, she was noted to have an increasing head circumference, and the head CT demonstrated static hydrocephalus. Developmentally, she has a global developmental delay affecting all domains. She currently walks unsteadily and feeds herself. She has no sphincter control, and she cannot talk or vocalize. Her parents are first-degree cousins, and they have a daughter and a son with congenital deafness and intellectual disability/ADHD. Her examination was significant for cutis laxa, hyperlaxity of joints, hepatomegaly, hypotonia, weakness, bilateral strabismus, oculomotor apraxia, inability to follow objects and poor vision. Other examinations were within normal limits. Her growth parameters at 9 years of age were weight 18 kg (<1 st percentile), height 111.5 cm (<1st percentile) and head circumference 55 cm (>97th percentile). Head CT at 1 year of age showed ventriculomegaly.

STK32C NM_173575.2:c.451G>C:p.(Val151Leu) (10DG0720)


A 10 years old boy who was born at full term via assisted vaginal delivery to 23 years old primigravida following an uneventful pregnancy with a birth weight of 3.2 kg. His Apgar scores were 7 and 10 at 1 and 5 minutes, respectively, and he cried immediately. Shortly after birth, he developed tachypnea, irritability and spastic movements of the upper limbs, and he was found to have mild hypocalcemia and hypomagnesemia. He stayed in NICU for three days and during that time he had weak suckling and feeding difficulty. The first abnormality that was noted by his parents was a motor delay at the age of 9 months. Developmentally, he has a global developmental delay. He sat at 15 months, walked at 22 months, said mama at 24 months and claimed stairs shortly after. At 3 years of age, he could speak only 10 words, and he could speak in two-word sentences at 4 years. He currently can jump on one leg, ride a tricycle, dress himself and tie his shoes. He can write his name and count to 10, and he is toilet-trained. His parents are third-degree cousins, and there is a family history of a similar condition in a paternal uncle and history of congenital glaucoma in another paternal uncle and his two daughters. His examination


revealed left eye strabismus, hypertonia and flat feet with the rest of his clinical examination being unremarkable. His growth parameters at 6 years of age were weight 18.4 kg (10th-25th percentile), height 107 cm (on the 5th percentile) and head circumference 51.1 cm (25th-50th percentile). His brain MRI showed periventricular, thalamic and perirolandic white matter changes, and MR spectroscopy showed a region of increased myoinositol in the left thalamus indicating gliosis with no lactate peak. His TSH has been persistently mildly elevated; however, he is not on thyroxine.

A 7 years old boy with brain malformation who is the uncle of 10DG0720. He was born at full term via NSVD to a G6P5+0 40 years old mother following an uneventful pregnancy. The perinatal and postnatal histories were unremarkable, and he was discharged on the second day. At the age of 7 months, he had his first seizure, and the frequency of his seizures increased with time. Developmentally, he has a profound developmental delay. He was at 10 months. He cannot walk or talk, and his speech is limited to mama. His parents are third-degree cousins. Physical examination showed microcephaly, brachycephaly, upturned ear lobules and hypertonia. His growth parameters at 7 years of age were weight 18.7 kg (on the 5th percentile) and head circumference was 48.5 cm (<1st percentile). Brain MRI showed right temporal lobe cortical dysplasia and EEG was consistent with partial seizure activity.

ZFAT NM_020863.3 :c.1199G>A:p.(Arg400Gln) (15DG2661)


A 2 years old girl with facial dysmorphism, global developmental delay, hypotonia, congenital hip dysplasia and failure to thrive. She was born at 37 weeks gestation via NSVD, and Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. Antenatal ultrasound revealed IUGR, ascites, pericardial effusion, dilated cisterna magna and hyper echogenic stomach wall. At birth, she underwent partial exchange transfusion due to polycythemia. Growth parameters at birth were weight 2.7 kg (10th -25th percentile), length 49 cm (25th-50th percentile) and head circumference 33 cm (10th -25th percentile). She was found to have PFO and PDA that closed spontaneously later on and bilateral DDH. Her parents are double first-degree cousins, and there is no family history of a similar condition. Her examination was significant for coarse facial features, hypertrichosis, thick bushy eyebrows, upslanting palpebral fissures, high forehead, a bilateral convergent squint, prominent nose, thin lips, prominent ears, prominent nasal tip, high narrow palate, fish mouth appearance, arachnodactyly, pectus excavatum, overlapping toes, hypotonia and generalized muscle wasting. Her growth parameters at 22 months of age were weight 8.8 kg (<1st

percentile, -2.71 SD), length 77 cm (on the 2nd percentile) and head circumference 44 cm (on the 1st percentile). Skeletal survey revealed generalized osteopenia, 11 pairs of ribs and bilateral DDH. Brain MRI, abdominal ultrasound, creatine kinase, newborn screening and CGH microarray were within normal limits. She had swallowing assessment, and she was found to have an aspiration of thin and thick fluids.

Gene/ Novelty Clinical Synopsis On Families Harboring Novel Variant


variant/ID

ADGRG1 NM_001145771.1:c.1000C>T:p.(Gln334*) (17DG0762)

Novel Variant

A 17 months old girl with global developmental delay and neonatal-onset hypotonia. She was born via NSVD with no perinatal or maternal risk factors. She has poor feeding and hypotonia since birth. Developmentally, she has a global developmental delay affecting all domains. She can coo, raise her head, grasp objects and roll over from side to side. The parents are first-degree cousins with two healthy daughters. Her examination was significant for severe hypotonia and weakness, but other examinations were within normal limits. Her last growth parameters at 17 months of age were weight 9.7 kg (25 th -50th

percentile), height 80 cm (on the 50th percentile) and head circumference 47.1 cm (50th -75th percentile). The brain MRI showed white matter abnormality.

ADK NM_006721.3:c.813dup:p.(Asn272Glufs*16) (16DG1608)

Novel Variant

A 4 years old girl who was born at full term via NSVD following an uneventful pregnancy. At birth, she was found to have hypotonia, poor feeding and ASD-II. She showed slow improvement in feeding within the first week of life. At 6 months of age, she started to have seizures that necessitate antiepileptic therapy. Developmentally, she has a global developmental delay. She cannot roll or sit. She can only make few scattered voices. Her parents are second-degree cousins once removed. Physical examination revealed central hypotonia with decreased power, tone and reflexes. Tandem MS and plasma amino acids revealed moderately elevated methionine and homocysteine that were persistently elevated. Ultrasound of kidneys and bladder showed a stable mild dilatation of the pelvicalyceal systems of both kidneys. Brain MRI showed areas of hypomyelination, reduced volume of the white matter and subcortical atrophy.

ARID1B NM_017519.2:c.5911G>T:P.(Glu1971*) (13DG0911)

Novel Variant

A 25 years old female with psychomotor delay, brain malformation and epilepsy. She was born at full term via NSVD with a birth weight of 1.5 kg. Pregnancy was complicated by gestational DM treated with insulin. She did not cry immediately after birth and kept in NICU for 3 days. She also started to have seizures at the age of two years that are described as tonic clonic with rolling of the eyes. Her first EEG was normal, and subsequent EEGs showed multifocal discharges. Developmentally, she had a global developmental delay as she sat at the age of 2 years and started to walk after the age of 3 years. Her speech is significantly delayed. Her IQ was estimated to be 55, and she was enrolled in special education program. She was noted to have aggressive behavior that led to drug treatment. Her parents are nonconsanguineous, and their other children are healthy. Physical examination at 25 years of age was significant for short stature, obesity, hypertelorism and depressed nasal bridge and her growth parameters were weight 78 kg, height 140 cm and BMI 39.7. She has a normal tone and power with hyperreflexia in the lower limbs. Brain MRI revealed agenesis of corpus callosum with bilateral colpocephaly. The lumbosacral scan showed spina bifida at L5 as well as upper two sacral vertebrae. Abdominal and renal ultrasound showed right ectopic kidney lying in the pelvis close to the urinary bladder on the right side and mild bilateral hydronephrosis. Pelvic MRI was done for secondary amenorrhea and showed


bicornuate unicollis uterus.ATP8A2 NM_016529.4:c.2600A>C:p.(His867Pro) (15DG2032)

Novel Variant

A 9 months old boy who was born via NSVD to a G1P0 mother following a pregnancy that was complicated by gestational hypertension. The first concern was hypotonia at three months of age. He does not seem to be achieving any milestones. There is no family history of a similar condition. His examination is significant for severe hypotonia, weakness, hyporeflexia and choreoathetosis. Muscle biopsy and brain MRI were reported as normal.

ATP8A2 NM_016529.4:c.322-1G>T (17DG0764)

Novel Variant

A 14 months old girl with hypotonia and global developmental delay. Her family history is significant for one affected sister and two abortions. The pregnancy and delivery were uneventful. She has a global developmental delay affecting all domains. On examination, she has no dysmorphic features, and she is interactive and following. Her head circumference at 14 months of age was 46 cm (50 th-75th

percentile). Her neurological evaluation was significant for severe hypotonia and hyporeflexia.

CDH15 NM_004933.2:c.2151+1G>A (17DG0765)

Novel Variant

An 11 years old girl who was born at full term via NSVD following an uneventful pregnancy. Her development has always been delayed. She walked at 30 months, and she started saying some words at 3 years. She has developmental dysplasia of the hip (DDH), and she underwent multiple surgeries to correct it. Her physical examination was significant for facial dysmorphia, prominent forehead, retrognathia, convergent squint and hyperextensible fingers. Growth parameters at 11 years of age were weight 51 kg (90th-95th percentile), height 152 cm (75th-90th percentile) and head circumference 51.5 cm (10th-25th

percentile).

CREBBP NM_001079846.1:c.4378C>T:p.(Arg1460*) (16DG0402)

Novel Variant

An 11 months old girl who was born at full-term via C-section due to failure to progress. Birth weight was 2.6 kg, and she was discharged from the hospital on the following day. She was noted at birth to have a cleft palate. She has had recurrent aspiration pneumonia that began within the second week of life led to several hospital admissions. Developmentally, she has a global developmental delay affecting all domains. She can roll over and hold her milk bottle, but she cannot sit, stand or say any word. Her parents are nonconsanguineous, and other siblings are healthy. On examination, her dysmorphic features include hypertelorism, excessive forehead hair, broad thumbs, three phalanges thumbs and bilateral prominent fingertip pads. Her growth parameters at 11 months of age were weight 5.1 KG and height 64 cm; both were below the 1st percentile. Her neurological assessment showed hyperreflexia and hypotonia, but other examinations were within normal limits. Brain MRI and EEG were reported to be normal.

CREBBP NM_001079846.1:c.881dup:p.(Asn294Lysfs*

Novel Variant

A 5 years old boy with dysmorphic features and developmental delay. He was born via an emergency C-section due to fetal distress and breech presentation to G3P2+0 30 years old mother following an uneventful pregnancy. Apgar scores were 6, 7, and 8 on 1, 5, and 10 minutes, respectively. He had cyanosis at birth, and he did not void for the first 24 hours. He also was noted to have bilateral undescended testes which were surgically corrected. He underwent a surgery to release his Achilles


56) (14DG0467)

tendon. Developmentally, he started to say dada and mama at 4 years of age. He currently crawls, feeds himself and recognizes parents and family. Parents are nonconsanguineous, and there is no family history of a similar condition. On examination, his dysmorphic features include hirsutism, prominent deformed ears, fixed flexion deformity of the right knee and ankle, wide first web space bilaterally, clenched overlapping toes, and prominent columella. His growth parameters at 5 years of age were weight 18 kg (50th – 75th percentile), height 98.5 cm (5th -10th percentile) and head circumference 48 cm (5th percentile). Brain MRI showed brain atrophy.

DDHD2 NM_015214.2:c.1891+2dup (16DG0325)

Novel Variant

A 15 months old boy who was born at 36 weeks of gestation via C-section to a primigravida 23 years old mother following a pregnancy that was complicated by poor maternal weight gain, oligohydramnios and pyelonephritis. Birth weight was 1.7 kg, and the baby was admitted to NICU for 40 days until his weight reached 2 kg. After discharge, he was noted that his skin was getting darker, and he was very floppy with poor feeding and frequent choking episodes. He has an episode of severe respiratory infection that led to a cardiopulmonary arrest. After successful resuscitation, he was admitted to PICU where he was found to have low cortisol and thyroid hormone levels. He has a history of two seizures. His development has always been delayed, and his development started to regress after that acute illness. He ruled over at 13 months of age, and he currently cannot sit, talk or walk. On examination, he has appendicular hypertonia, axial hypotonia and hyperreflexia with a clonus. His growth parameters at 15 months of age were weight 9.5 kg (25th -50th percentile), height 67.5 cm (<3rd percentile) and head circumference 45.3 cm (on the 10th

percentile). Brain MRI showed significant white matter changes.

DHCR7 NM_001163817.1:c.778C>T:p.(Arg260Trp) (15DG0305)

Novel Variant

A 3 years old boy who was born at 32 weeks of gestation with multiple anomalies. Growth parameters at birth were weight 2.4 kg and head circumference 30 cm (< 3rd percentile). Developmentally, he was able to stand with support at the age of 26 months, and he currently can say only single words. His parents are first-degree cousins with three healthy children, and they had a daughter who died for an unknown reason. His examination was significant for left cleft lip and U shape cleft palate, flat face, micrognathia, syndactyly between the fourth and fifth metacarpals and metatarsals and flexion deformity with ulnar deviation of the metacarpophalangeal and interphalangeal joints, bilateral rocker bottom feet deformity and bowing of the lower extremities. Brain MRI was reported to be normal. Cardiac echocardiogram showed small atrial septal defect and small patent ductus arteriosus. His skeletal survey showed sclerosis of the skull sutures with prominent occiput, J-shaped sella, short sternum and small facial bones.

DHDDS NM_024887.3 c.452A>G: p.(Asn151Ser)

Novel Variant

A 14 years old girth with a static encephalopathy, seizure disorder and profound developmental delay. She was born at full term via NSVD to a healthy mother following a pregnancy that was complicated by decreased fetal movements. Her birth weight was 3 kg, and she cried immediately. The perinatal and postnatal histories were unremarkable, and she was discharged on the second day. The first concern was


(12DG2165)

floppiness and abnormal head movements in the first few months of life. During the 4th months of life, she had a tonic clonic seizure, and all investigations at that time were negative. Developmentally, she has a profound developmental delay. She currently can partially control her head, and she cannot sit, stand, walk, talk, babble or use her hands. Her parents are a first-degree consanguineous couple with a history of abortion and another healthy son, and there is a family history of a similar condition in a deceased maternal uncle, a deceased cousin and two other similarly affected cousins. Her physical examination was significant for microcephaly, deep-set eyes, prominent nasolabial fold, prominent chin, dental anomalies, nystagmus, short 4th and 5th metacarpal bones, bilateral talipes equinovarus, deep plantar crease, appendicular hypertonia and hyperreflexia. Ophthalmological examination showed mild disc pallor that is mainly on the right side and exotropia of the right eye. Other examinations were within normal limits. Her growth parameters at 12 years of age were weight 33 kg and head circumference 47 cm. Brain MRI showed signs of atrophy of frontal lobes with mild atrophy of parietal lobes, and SPECT scan revealed reduced cerebral perfusion of both frontoparietal lobes. Visual evoked potential and ERG showed cortical blindness, and BAEP showed a severe hearing loss.Her cousinA 21 months old boy with microcephaly, seizure disorder and developmental delay. He was born at full term via NSVD with Apgar scores of 9 and 9 at 1 and 5 minutes. He developed seizures on the second day of life, and he was admitted to NICU and started on Phenobarbital. Serum amino acid, urine organic acid, NH3 and brain ultrasound were unremarkable. EEG showed left central sharp and spikes, and brain MRI showed diffuse low T1 and high T2 signal intensity in white matter. His seizures ceased, and he was discharged home on phenobarbital. Developmentally, he has a global developmental delay. He sat with support at 7 months. He currently can crawl, but he cannot stand, cruise or walk. His speech is limited to baba only. His parents are consanguineous with a deceased son with a seizure disorder and developmental delay. His physical examination was significant for microcephaly (Head circumference 45 cm, <3rd

percentile), appendicular hypertonia and hyperreflexia. Brain MRI at 10 months of age showed bilateral symmetrical peritrigonal focal T2 white matter high signal intensities.

DNAH14 NM_001373.1c.9808C>T:p.(Arg3270*) (14DG1743)

Novel Variant

A 6.5 years old boy who was born at full term via NSVD with normal growth parameters at birth. Antenatal and perinatal history was unremarkable, and he was discharged home on the following day. His gross motor development has been appropriate for age. However, he seems to have a delay in fine motor and language domains. He still has immature finger grasp and cannot feed himself or dress himself. Parents are first-degree cousins, and they have two other children with intellectual disability. His last growth parameters at 6 years of age were weight 16.6 kg (10th-25th percentile), height 113 cm (on the 25th

percentile) and head circumference 48.4 cm (5th-10th percentile). He has no dysmorphic features apart


from bilateral clinodactyly. EHMT1 NM_024757.4:c.2968C>T:p.(Gln990*) (17DG0766)

Novel Variant

A 13 years old boy who was born to first-degree cousins with a family history of a similar condition. He has a severe intellectual disability, autism, motor delay, absent speech and dysmorphic facial features. On examination, his current growth parameters were weight 60.8 kg (90th -95th percentile), height 159 cm (on 75th percentile) and head circumference 43 cm (<1st percentile). Other examinations were within normal limits. Brain MRI showed dysplastic corpus callosum.

ERCC8 NM_000082.3: c.427del:p.(Thr143Glnfs*17) (17DG0767)

Novel Variant

A 14 months old boy with severe microcephaly, global developmental delay, severe photosensitivity and congenital cataract. Family history is significant of two deceased sisters with a similar phenotype.

FBN1 NM_000138.4:c.2626_2634del:p.(Cys876_Ser878del) (16DG0105)

Novel Variant

A 6 years old girl who was born to G3P2 30 years old mother following an uneventful pregnancy. She has been healthy, and her development is appropriate for age. She was found to have dislocated lenses and myopia that led to the identification of her condition. Her parents are nonconsanguineous, and there is no family history of a similar condition. On examination, her growth parameters at 6 years of age were weight 28.7 kg (>97th percentile), height 132 cm (>97th percentile) and head circumference 54 cm (on 97th

percentile). She has a high arched palate, arachnodactyly, subluxated lenses and positive thumb and wrist signs. Echocardiogram revealed a doming of the mitral valve with minimal regurgitation.

FMN2 NM_020066.4:c.3335delC:p.(Pro1112Leufs*163) (17DG0768)

Novel Variant

An 11 years old boy who was born at full-term via NSVD. He was found to be microcephalic at birth with a head circumference of 28 cm (<1st percentile). He developed seizures and has shown a global developmental delay affecting all domains and his estimated IQ was 50-56. Developmentally, he can only say a few words; he sat at 1 year and walked at 2 years. Parents are second-degree cousins with three other healthy children. On examination, his dysmorphic features include sloped forehead and prominent nose. His last growth parameters at 11 years of age were weight 25 kg, height 132 cm and head circumference 40 cm, all below the 3rd percentile. Brain MRI showed pachygyria, thin corpus callosum, lobar holoprosencephaly and Arnold Chiari malformation type I as well as creatine peak in MR spectroscopy.

GJC2 NM_020435.3:c.755A>G:p.(His252Arg) (15DG2206)

Novel Variant

A 17 years old girl with neuroregression that started at 4 years of age. She had been developmentally normal until the age of 4 years when she started to gradually lose her ability to walk and talk, and she is currently wheelchair-bound. She communicates through nodding her head. She also has developed seizures, but they have been under control. The parents are first-degree cousins, and they have three other affected children and three deceased children who died for an unknown reason. On examination, her


growth parameters were weight 32 kg (<3rd percentile) and head circumference 49 cm(<3rd percentile). She has an ulnar deviation of the hands. She also has hyperreflexia of the extremities and strabismus. MRI showed mild leukodystrophy. Skin biopsy showed inclusion bodies.

GLRX5 NM_016417.2:c.197A>C:p.(Gln66Pro) (13DG1665)

Novel Variant

A 30 months old deceased boy who was born at full term via NSVD following an uneventful pregnancy. Birth weight was 3.3 kg, and he was discharged on the second day. He was apparently healthy and developing normally until 9 months of age when he was noted to have bilateral strabismus. A month later, he became unable to follow and was found to be blind, and then he started to have swallowing problems with solids that progressed to liquids as well. A few months later, he developed frequent jerks which progressed to generalized tonic-clonic seizures, and he started to lose milestones. Extensive investigations were normal. He eventually had a global developmental delay. His clinical course was complicated with multiple hospitalizations and ICU admissions due to respiratory infections. The parents are second-degree cousins once-removed, and they had a child who died due respiratory complications at 8 months of age. On examination, his growth parameters at 30 months of age were weight 8.5 kg (25th percentile), height 83 cm (at the 50th percentile) and head circumference 43 cm (<3rd percentile). His physical examination was significant for microcephaly and severe hypotonia. Other examinations were within normal limits. EEG was remarkable for hypsarrhythmia and multifocal epileptic discharges. Brain MRI and MRS demonstrated diffuse extensive abnormal T2 hyperintensity of both cerebral and cerebellar hemispheres and the corpus callosum as well as the posterior limb of the both internal capsule and the paramedian tracts. It also showed atrophied thalami and restricted water diffusion with multifocal areas of necrotic appearance in the periventricular region and the centrum semiovale, bilaterally.

GTF3C3 NM_012086.4:c.139082+3A>G (15DG0315 )

First confirmatory mutation to a published gene

A 13 months old girl who was born at full term via NSVD to a G2P0A1 mother. Pregnancy was complicated by recurrent UTIs and premature contractions. The perinatal and postnatal histories were unremarkable, and she was discharged on the second day. Growth parameters at birth were weight 2.9 kg and head circumference 35 cm (50th-75th percentile). The first concern was a poor growth and absent vision fixation. Developmentally, she started sitting with support, reaching and transferring objects at 11 months. On examination, her dysmorphic features include facial asymmetry, bilateral temporal narrowing, epicanthal folds, upslanting palpebral fissures, bulbous nose, and full cheeks. She has ataxic movement of the head and hypotonia. Her Hearing assessment was normal, and other examinations were within normal limits. Her growth parameters at 13 months of age were weight 7.1 kg (<3rd percentile), height 66.8 cm (<3rd percentile) and head circumference 39(<3rd percentile).

IRX5 NM_005853.5:c.805dup:(p.

Novel Variant

A 5 years old boy with dysmorphic facial features, hypertelorism, downslanting eyes, small ears, epicanthal folds, short neck, global developmental delay and mild autistic features. The parents are consanguineous, and they have another affected daughter.


(Arg269Profs*187) (15DG0633)

LAMA1 NM_005559.3:c.7437dup:p.(Gly2480Argfs*11) (16DG0051)

Novel Variant

A 12 years old boy who was born at full term via NSVD to a G2P1 mother following an uneventful pregnancy. He was noted to have an abnormal roving eye movement in infancy, and it was found that his retina is severely damaged, bilaterally. His motor and cognitive functions are appropriate for age. His parents are first-degree cousins, and they have a daughter with a similar condition and occipital encephalocele and two sons with intellectual disability. His growth parameters at 12 years of age were weight 39 kg (50th -75th percentile), height 153 cm (50th -75th percentile) and head circumference 53 cm (25th – 50th percentile). He does not have dysmorphic features. Brain MRI showed nonspecific white matter changes.

LAMA2 NM_000426.3:c.2096G>T:p.(Arg699Met) (17DG0769)

Novel Variant

A 12 years old boy who was born at full term via NSVD to a G4P3 35 years old mother following an uneventful pregnancy. He was noted to be hypotonic shortly after birth, but it was only during the second month of life when he was found to have high CK in addition to his hypotonia, so the clinical diagnosis of merosin-deficient muscular dystrophy was made. Developmentally, he has a global developmental delay, and his motor and cognitive skills seem to be severely delayed. He is still unable to sit unsupported. His past medical history is notable for nephrosis that developed suddenly at 4 years of age that has been treated with steroids. His parents are consanguineous, and they have a younger child with severe hypotonia. Physical examination revealed severe underweight and a borderline OFC (6th percentile). His dysmorphic features include plagiocephaly, open bite, multiple contractures of hands and knees joints, severe scoliosis and one large café au lait macule in the lower back. He also was found to have severe hypotonia and areflexia. Other examinations were within normal limits. Echocardiogram showed a normal cardiac function.

LAMB2 NM_002292.3:c.4276dupG:p.(Ala1426Glyfs*6) (14DG1320)

Novel Variant

A 2 months old deceased boy with pinpoint pupils, right eye microcornea and microphthalmia, congenital nephrotic syndrome, pulmonary hypoplasia and renal failure. He was born at full term via NSVD, and he cried immediately after birth. Apgar scores were 6, 8 and 9 at 1, 5, and 10 minutes, respectively. The antenatal ultrasound at 32 and 37 weeks of gestation showed anhydramnios and bilateral echogenic dilated dysplastic kidneys. At birth, he was noted to have pinpoint pupils and right eye microconia, and he was admitted to high dependency unit. Chest X-ray showed severe pulmonary hypoplasia, and echocardiogram showed an ostium secundum atrial septal defect with a left to right shunt and large PDA. Renal ultrasound showed enlarged dysplastic echogenic kidneys. He did not pass urine for the first 12 hours of life. His parents are first-degree cousins, and they have another healthy child and a history of abortion. On examination, he has mild paleness, subtle dysmorphic features, depressed nasal bridge,


unilateral concave face and bilateral talipes equinovarus deformity. His chest examination was remarkable for respiratory distress, subcostal and intercostal recession, accessory muscle use and bilateral decreased air entry. Other examinations were within normal limits.

METTL5 NM_014168.2:c.224+1G>A (11DG1842)

Novel Variant

This is a baby girl who was born at 36 weeks gestational age via C-section to primigravid 24 years old healthy mother. She was admitted to NICU for symmetric IUGR and mild respiratory distress. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively, and growth parameters at birth were weight 1.92 kg (<1st percentile), length 48 cm (25th-50th percentile) and OFC 29.5 cm (<1st percentile). On examination, her dysmorphic features include oligodactyly and dysplasia of the digits in the right hand (4 digits), Cutis aplasia in the scalp, posteriorly rotated ears, prominent nose and micrognathia. Her last growth parameters were all below 3rd percentile, and other examinations were within normal limits. Brain MRI was reported to be within normal limits. Skeletal survey showed 5 metacarpals with 3 hypoplastic fingers in the right hand as well as a claw appearance of a part of the little finger. The left hand is unremarkable.

MFSD8 NM_ 152778.2:c. 1354_1369del:P.(Val452*) (16DG0485)

Novel Variant

A 13 years old boy who was born at full term via NSVD following an uneventful pregnancy. He was developmentally normal until two years of age when he started to regress by losing his ability to speak. He sat with support at 4 months, talked by 9 months, and walked at 13 months. He is currently nonexpressive verbally, although he does seem to retain some verbal comprehension. He started to have seizures at 3 years of age. His seizures seem to be a combination of absence seizures and generalized tonic-clonic seizures which can occur even while he is walking and causing him to fall on the floor. He has an older sister who has been through the same course. His past medical history is noteworthy for a herniorrhaphy at age 4 months of age. His physical examination revealed appendicular hypertonia and hyporeflexia. He does not have dysmorphic features, and other examinations were within normal limits. His and his sister’s brain MRI were reported as normal. An experimental PET scan was done for him and it showed increased radiotracer binding in the bilateral basal ganglia and right hippocampus.

MICU1 NM_001195518.1: c.547C>T: p.(Gln183*) (15DG0299)

Novel Variant

A 17 years old boy with intellectual disability, seizure disorder and ADHD. He was born to consanguineous parents without a history of prenatal or postnatal complications. He had a global developmental delay that was mainly in cognitive functions with poor attention and hyperactivity. He also has seizures that started at 6 years of age with semiology of a partial component. His seizure disorder has been refractory to multiple antiepileptic medications. He later developed new episodes of dystonic movements, and he started to deteriorate clinically and his dystonic symptoms were getting worse. EEG was consistent with a partial seizure. Initial brain MRI was reported to be normal, and a second MRI three years later showed bilateral tonsillar herniation.

NAXE NM_144772.2:

Novel Variant

A 4 years old deceased boy who was born at full term via NSVD to first ‐degree cousins following an uneventful pregnancy. He was developing normally for the first two years until he had an episode of


c.262G>T:p.(Gly88Trp) (12DG2311)

stiffness that turned to be seizures. Extensive seizure and metabolic investigations were negative at that time, including brain MRI. He also started to regress in his motor skills and had dystonia and ataxia. Months later, he had two severe episodes of seizures, high-grade fever, dystonia, hypotonia and hyperextension of the neck. Brain MRI showed massive hemorrhagic infarction of nonvascular distribution pattern involving both posterior occipitoparietal regions within the brainstem area and cerebellum. Thorough investigations did not show a source of infection, and he subsequently died due to progressive cerebral edema and tentorial herniation. Muscle biopsy showed mild lipid myopathy with type 2 muscle fiber atrophy, with no morphological evidence of mitochondrial disease. He had two other siblings who died of unknown cause with a similar course.

NKX6-2 NM_177400.2:c.196delC:p.(Arg66Glyfs*122) (16DG1123)


A 10 years old girl with encephalopathy, developmental delay, strabismus and scoliosis. MRI showed hypomyelination. The parents are first-degree cousins with another similarly affected child.

OCRL NM_000276.3:c.2479C>T:p.(Gln827*) (15DG0115)

Novel Variant

A 1-year-old boy with bilateral cataract, global developmental delay, nephrocalcinosis, proteinuria with normal renal function, G6PD and hepatic calcification. Developmentally, he has a global developmental delay. His parents are first-degree cousins, and they have another four healthy children with no family history of a similar condition. His examination was significant for sparse hair, fair hair, deep seated eyes, small eyes, hypotonia, hyperreflexia, reduced muscle mass. Growth parameters at 12 months of age were weight: 5.3 kg, Length: 61 cm, head circumference: 40.5 cm. Other examinations are within normal limits. Head CT showed mild asymmetrical dilation of both lateral ventricles due to central atrophy. Abdominal ultrasound showed nephrocalcinosis and hepatic calcification. He was found to have hypocalcemia (0.61 mmol/L), hypomagnesemia (0.3 mmol/L), hypophosphatemia (6.7 mmol/L) and hypercalciuria

PCNT NM_006031.5:c.1879G>C:p.(Glu627Gln) (17DG0772)

Novel Variant

A 10 years old with ADHD, autistic features, cold intolerance, sloping forehead, microcephaly, brittle hair, esotropia, failure to thrive, muscle weakness and frequent falls.

PHIP NM_017934.5:c.577C>T:p.

Novel Variant

A 10 years old girl who was born at full term via NSVD to 29 years old primigravida following a pregnancy that was complicated by toxoplasmosis. After birth, she did not pass meconium and developed jaundice, and she was admitted to the nursery for a week. She had recurrent UTI that was secondary to

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=Nucleotide&term=NM_006031&doptcmdl=GenBank&tool=genome.ucsc.edu




(Arg193*) (15DG2307)

left ureterovaginal fistula and VUR. She also had been floppiness since birth. Developmentally, she had a global developmental delay. She walked at 20 months and said dada and mama at 3 years of age. She has difficulties in school and memorization. Her IQ was estimated to be 70-79. Her parents are nonconsanguineous but they are from the same tribe, and they have a healthy son. There is a history of intellectual disability in a paternal cousin. Her examination revealed increased laxity of the major joints and mild camptodactyly of fingers, and other examinations were within normal limits.

PPP2R1A NM_014225.4:c.190G>A:p.(Glu64Lys) (15DG2336)

Novel Variant

This is a 30 months old boy who was the product of a full-term pregnancy, and his growth parameters at birth were weight 2.2 kg (<3rd percentile), length 45 cm (<3rd percentile) and head circumference 32 cm (on the 3rd percentile). He was noted to have hypospadias, undescended testes, hypotonia and delay development. He also has been found to have central sleep apnea requiring O2 by nasal cannula. Parents are not cousins with another healthy child and another affected child. They have had a child with anencephaly and abortion. There is a family history of anencephaly on the maternal side, and his father had a delayed speech as a child. His dysmorphic features are epicanthus inverses, small nose with a high nasal bridge, prominent ears, long columella, hypoplastic alae nasi, hypotelorism and scoliosis. He was found to have omega-shaped epiglottis. Brain MRI showed slightly prominent ventricular system.

PPP2R5D NM_180977.2:c.274G>A:p.(Glu92Lys) (15DG0837)

Novel Variant

A 23 months old girl who was born via NSVD to G4P3 36 years old mother following an uneventful pregnancy. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. She seized at the 10 th hour of life, and she was admitted to NICU. Comprehensive investigations were carried out, and they were negative. She continues to have break-through seizures despite a trial of multiple antiepileptic drugs. On examination, her growth parameters at 23 months were weight 9.6 kg (10 th -25th percentile), height 79.5 cm (10th -25th percentile) and head circumference 51 cm (>98th percentile). Her dysmorphic features are macrocephaly, prominent forehead, downslanting epicanthal folds, anteverted nares, one café au lait spot and significant axial and appendicular hypotonia. Other examinations were within normal limits.

PRMT7 NM_019023.2:c.190C>T:P.(Gln64*) (16DG0201)

Novel Variant

These are two siblings with global developmental delay, a boy 42 months old and a girl 16 months old. They were born at full term via a C-section and vaginal delivery, respectively. They both have hypotonia and autistic features, and IQ was estimated to be 35 for both. Their parents are first-degree cousins, and they have had two deceased children with a similar condition. Their shared dysmorphic features are brachydactyly and microcephaly. Brain MRI and EEG were normal. Other examinations were within normal limits.

RELN NM_005045.3:c.3711+2T>C (14DG0959)

Novel Variant

A 12 years old girl with profound developmental delay, brain malformation and glaucoma. She was born via NSVD to G3P2+0 35 years old mother following an uneventful pregnancy. Neonatal history was unremarkable. At 4 months of age, the mother was concerned that the baby was too floppy, and her eyes seemed hazy that led to an eye surgery at that time. Developmentally, she has a global developmental


delay. She is still unable to sit, and she can say mama and dada. Her parents are first-degree cousins, and she has a sister with a similar condition. Her growth parameters at 12 years of age were weight 23.5 kg (<3rd percentile) and head circumference 51.5 cm (10th -25th percentile). Her dysmorphic features include hypertelorism, bulbous nasal tip and buphthalmos. She has hypertonia and spasticity. MRI showed lissencephaly and Cerebellar hypoplasia.

RFT1 NM_052859.3:c.1154A>G:p.(Asn385Ser) (15DG0298)

Novel Variant

A baby girl who was born at 36 weeks of gestational age via a C-section due to breech presentation to a G6P4 A1 L3 mother. Antenatal ultrasound revealed polyhydramnios. Apgar scores were 6,8 & 9 at 1,5 & 10 minutes, respectively, and birth growth parameters were weight 2.4 kg, length 49 cm and head circumference 34 cm. She was admitted to NICU immediately after birth due to significant hypotonia and respiratory distress. Her parents are a first-degree consanguineous couple, and they had two deceased children with hypotonia and encephalopathy. On examination, there is no gross deformity, but she has a myopathic face, opened mouth, froglike posture, a paucity of limb movements, hyporeflexia, significant head lag, truncal hypotonia and thinning of the distal part of the legs with a mild inward curvature of both legs. Other examinations are within normal limits.

SCN1A NM_001165963.1:c.437C>A:p.(Thr146Lys) (16DG0697)

Novel Variant

An 11 years old boy who was born to a G3P2 32 years old mother following an uneventful pregnancy. He had his first seizure at 4 months of age, and they were progressing in term of severity and frequency and reaching a peak at the age of three years. He was developing normally until three years of age when he started to lose his milestones. His parents are first-degree cousins, and there is a history of seizures on the paternal side. His growth parameters at 11 years of age were weight 45.5 kg (75 th-90th percentile), height 144.7 cm (50th-75th percentile) and head circumference 52.7 cm (25th-50th percentile). His physical examination was significant for hyporeflexia, and he did not have dysmorphic features. His brain MRI was normal and EEG showed dysrhythmia with evidence of encephalopathy.

SETD5 NM_001080517.1:c.892_907del:p.(Ile298Glyfs*32) (17DG0774)

Novel Variant

This is an 11 years old boy with intellectual disability, bilateral postaxial polydactyly, microcephaly, abnormal hair, aortic dilatation (AR), atrioventricular septal defect, right undescended testis, left upper lid moderate-to-severe ptosis, short palpebral fissures that are more severe in the left, dysmorphic facial features and short stature. His parents are consanguineous, and his father and one of his brothers are similarly affected without the cardiac component. Skeletal Survey showed osteopenia, and cardiomegaly and pulmonary congestion

SETD5 NM_001080517.1:c.2476+1G>A (17DG0775)

Novel Variant

A 7 years old girl with a developmental delay, nystagmus and ADHD. She was born at full term via NSVD to a G9P6 SB2 40 years old mother following an uneventful pregnancy. The perinatal and postnatal histories were unremarkable, and she was discharged on the second day. The first concern was a developmental delay that was recognized in late infancy. She walked at 18 months, and she started saying mama and dada at 12 months, but she currently has less than 100 words vocabulary. She is not toilet


trained. Her IQ was estimated to be 77. Her parents are consanguineous with a family history of a similar condition in two siblings and four cousins. Her father seems to be mildly affected. Her physical examination showed a thin body built, and other examinations were within normal limits. Her growth parameters at 7 years and 4 months were weight 16.1 kg (<3rd percentile), height 113.4 cm (3 rd-10th

percentile) and head circumference 53 cm (75th-90th percentile). Brain MRI showed thickened corpus callosum, mild cerebellar atrophy and small hippocampi.

SPG20 NM_001142294.1:c.988A>G:p.(Met330Val) (15DG0749)

Novel Variant

An 8 years old boy who was born via an induced vaginal delivery to G3P0 A2 23 years old mother. Neonatal history was uneventful, and they were discharged on the third day. His motor development has been appropriate for age, but his language has always been delayed. He was 2 years old when his parents started to feel his gait was unstable, and they were concerned about his language delay. His IQ was estimated to be 70. He has a 6 years old sister with a similar condition, and there is a family history of intellectual disability. On examination, he has no dysmorphic features, and his growth parameters at 8 years of age were weight 18.7 kg (10th percentile), height 113.5 cm (3rd -5th percentile) and head circumference 51 cm (25th- 50th percentile).


Novel Variant

A 7 years old girl with failure to thrive. She was born via C-section at 39 weeks of gestational age due to breech presentation to G2P1+0 23 years old mother following an uneventful pregnancy. Growth parameters at birth were weight 2.6 KG, length 48 cm and head circumference 34.5 cm. The first concern was a poor weight gain at early months of life, and she underwent a full clinical evaluation that was negative. Developmentally, she started to walk at 14 months and started saying mama and dada at 2 years of age. She can now speak in full sentences but strangers find some difficulties in understanding her speech secondary to her dysarthria. Gross motor skills are appropriate for age. Her IQ was estimated to be 90 at 6 years of age. She also had atrial fibrillation since very young age. Parents are first-degree cousins, and she has a brother with developmental delay. There is a family history of intellectual disability in a paternal cousin. Her examination was significant for subtle dysmorphic features, dental anomalies, ataxic gait, hyperreflexia and metatarsus adductus. Her growth parameters at 7 years of age were weight 12.7 kg (<3rd percentile), height 102.2 cm (<3rd percentile) and head circumference 50 cm (25th-50th percentile).


Novel Variant

A 7 years old boy who was born at full term via NSVD to a G2P1 33 years old mother following an uneventful pregnancy. His birth weight was 2 kg. The perinatal and postnatal histories were unremarkable, and he was discharged on the second day. He had jaundice that started within 24 hours and resolved spontaneously. He had recurrent respiratory infections that led to multiple hospital admissions. He was also found to have developmental dysplasia of the hip (DDH) and growth hormone deficiency. Developmentally, he has a global developmental delay. He sat at 1 year, cruised at 18 months and walked after he has a surgical repair of his DDH. He currently can grasp and transfer objects and say mama and


babbling, but he can understand and follow commands. Parents are second-degree cousins, and they have another affected male child. On examination, his growth parameters at 7 years of age were weight 11.6 kg, height 94.5 cm and head circumference 46.5 cm, all below the 5th percentile. His dysmorphic features include a bulbous nose, thin upper lip, right elbow deformity, drooling and café au lait spots on his back and right thigh. Other examinations were within normal limits. Brain MRI was reported as normal, and extensive laboratory investigations were within normal limits.


Novel Variant

A 19 months old boy who was born via NSVD following an uneventful pregnancy. He presented with similar clinical features as his brother. He had a migratory seizure at 2 months of that was refractory to multiple antiepileptic medications and was associated with severe oropharyngeal dysphagia. He currently has a poorly controlled seizure on three AED. He has severe gastroesophageal reflux and swallowing dysfunction that needed fundoplication and G-tube insertion. Clinical examination revealed microcephaly and spasticity with poor visual fixation. His growth parameters at 19 months of age were weight 12 kg (50th – 75th percentile), length 71 cm (<3rd percentile) and head circumference 44 cm (<3rd percentile). Brain MRI showed appropriate for age myelination but with diffuse volume loss and prominent subarachnoid spaces anteriorly as well as a thin corpus callosum. MRS was reported as normal. The EEG showed generalized multifocal spikes more in the temporal region and slow background with lack of sleep features as well as continuous subclinical seizures.

SPTBN4 NM_020971.2:c.3394del:p.(His1132Thrfs*39) (16DG1625)


A 5 years old girl with swallowing difficulty, recurrent chest infections and developmental delay. She can only say 4 words. Her parents are first-degree cousins, and there is no family history of a similar condition. Her growth parameters at 5 years of age were weight 9.4 kg, height 82.5 cm and head circumference 46 cm, all below the 3rd percentile. Her physical examination was significant for a blue sclera, hypotonia and hyporeflexia. Vision and hearing were normal, and other examinations were within normal limits. The brain MRI was grossly normal with diffuse T-2 hyperintensity in subcortical white matter.

STIL NM_001048166.1:c.3552_3553del:p.(Cys1184*) (17DG0779)

Novel Variant

A 13 years old boy with ADHD, GDD, failure to thrive, microcephaly, dysmorphic facial features, short stature, ataxia, dystonia, hypertonia, spasticity, visual impairment and seizures. He was born to consanguineous parents with no family history of a similar condition. Head circumference at birth was 28 cm (<1st percentile). Brain MRI showed partial agenesis of the corpus callosum, absent septum pellucidum and abnormal cortical migration with pachygyria.

TECPR2 NM_001172631.1:c.571C>T:

Novel Variant

An 8 years old girl who was born at full term via NSVD to G4P2+1 33 years old mother. A decrease in fetal movements was noted during pregnancy, and her birth weight was 2.8 kg. After birth, she was noted to be floppy with poor sucking. At one month of age, she started to have choking episodes that turned to


p.(Gln191*) (09DG00835)

be due to severe GERD, and Niessel fundoplication was performed. Aspiration problems persisted, and the fundoplication procedure was repeated later. She also has developed seizures and continues to seize daily despite multiple attempts to control her seizures with medications. Her seizures’ semiology appears to be as opisthotonic posturing. She also has bronchial asthma. Her parents report that she barely can feel pain, and she has no tears when she cries even though she has normal sweating. She demonstrates a self-mutilating behavior by scratching her face. Parents are consanguineous, and there is no family history of a similar condition. Currently, she has a developmental delay affecting all domains, and her IQ was estimated to be 20-30. She can vocalize, but cannot talk. She can walk although her gait is unstable. On examination, she has poor growth with a significant microcephaly. She has subtle dysmorphia characterized as hypotelorism and tapering of fingers. MRI showed thinning of the corpus callosum and mild atrophy of the cerebellar vermis.

TRAK1 NM_001042646.2:c.287-2A>G (16DG0971)


A 10 months old deceased boy who was born at full term via NSVD with a birth weight of 2.5 kg. He was admitted for one week in NICU because of transient respiratory distress and questionable sepsis. He started to have focal seizures at 6 months of age. He was admitted to PICU due to a persistent seizure that needed multiple antiepileptic medications, and he stayed there for three months because of failure to extubate and poorly controlled epilepsy. Developmentally, he had a global developmental delay. His parents are first-degree cousins with another son who has a similar condition. His physical examination revealed a microcephalic child with axial hypotonia and generalized spasticity. Other examinations were within normal limits. His growth parameters at 10 months of age were weight 8 kg (on the 3 rd percentile), height 61 cm(<1st percentile) and head circumference 41 cm (<1st percentile). Brain MRI showed generalized brain atrophy, bilateral diffusion restriction in the posterior limbs of the internal capsule, and symmetric foci of diffusion restriction in the midbrain and the dorsal brainstem along the sensory white matter tracts. MRS showed raised choline levels in the white matter. EEG showed generalized encephalopathic state and evidence of partial seizure.

TRAK1 NM_001042646.2:c.1759dup:p.(His587Profs*32) (17DG0780)


A 9 months old deceased boy who was born at full-term via C-section due to meconium-stained liquor and fetal distress. He was admitted to NICU immediately after birth where he developed convulsions and jerky movements. His seizures have been difficult to control, and he is on multiple medications. The parents are first-degree cousins once removed, and they had a daughter with a similar course that passed away at the age of 16 months. His examination was significant for dysmorphic features and sluggish pupils. Brain MRI showed diffuse brain atrophy and delayed myelination of white matter.

TRAPPC9 NM_031466.4:

Novel Variant

An 8 years old boy who was born at full-term via C-section due to placenta previa following an uneventful pregnancy. Birth growth parameters were within normal limits with a head circumference of


c.2785C>T:p.(Arg929*) (17DG0781)

33 cm (50th percentile). The first abnormality was noted at 9 months of age when he was found to have delayed development. He has a global developmental delay affecting all domains, and his IQ was estimated to be 55. He can currently walk with a wide base gait. His parents are a first-degree consanguineous couple with five healthy children, and there is no similar condition in the family. On examination, his current growth parameters at 8 years of age were weight 30 kg (75 th – 90th percentile), height 125 cm (50th -75th percentile) and head circumference 48 cm (< 3rd percentile). His dysmorphic features include deep-set eyes, high nasal bridge, frontal bossing, prominent occipital protuberance, large central teeth, short fingers, prominent jaw and flat feet. Other examinations were within normal limits. EEG was reported to be normal, and brain MRI showed periventricular hypomyelination with a prominent retrocerebellar cistern. Skeletal survey revealed relative decreased height of the cervical vertebral bodies, straightening of the lumbosacral spine, bilateral coxa valga deformity, depression of the medial tibial plateau and hypertrophy of the medial femoral condyle on both knees, over pneumatization of the mastoid air cells, shortening and broadening of the small bones of the hands as well as the feet and growth arrest lines.

UBE3A NM_000462.3:c.504delG:p.(Val170Leufs*9) (14DG0647)

Novel Variant

(14DG0647) 11 years old boy who was born at full term via NSVD following an uneventful pregnancy. His birth growth parameters were weight 2.75 kg and head circumference 31.5 cm. He has a global developmental delay, microcephaly and seizures. Parents are first-degree cousins, and they have another affected son. There is a family history of hearing loss on the maternal side. (14DG0648) A 9 years old boy who was born at full term via NSVD following an uneventful pregnancy. Birth weight was 2.5 kg, and he was noted to have microcephaly. He also has a global developmental delay and seizures.

VWA3BNM_001164416.1:c.124C>T:p.(Arg42*) (17DG0782)

Novel Variant Autism spectrum disorder and speech delay

WDR81 NM_001163809.1:c.5335C>T:(p.Arg1779*) (17DG0783)

Novel Variant

This is a 13 months old boy with severe microcephaly, Dandy-Walker malformation, spasticity, GDD, developmental regression and failure to thrive. Parents are consanguineous, and there are no affected siblings. Head circumference at birth was 27 cm and at 1 year was 34 cm.

ZDHHC9 NM_016032.3:c.487+5_487+

Novel Variant

A 10 years old boy who was born at full term via NSVD as part of a twin gestation following an uneventful pregnancy. Developmentally, he had a global developmental delay. He started to walk at the age of 5 years with ataxic gait, and he also was delayed in his speech. His speech is currently difficult to


19del(14DG2158)

understand. His parents are first-degree cousins with another two affected sons. Physical examination revealed subtle dysmorphic features in the form of an elongated face, large prominent ears and high-arched palate without neurocutaneous marks. He has hypertonia and hyperreflexia in all extremities, but other examinations were within normal limits. MRI brain and cervical spine showed moderately decreased peritrigonal cerebral white matter with thinning of the body of the corpus callosum and focal syrinx in mid thoracic region.

static-content.springer.com10.1007/s00… · Web viewGene/variant/ID. Novelty. Clinical Synopsis On...

Documents

Transcript of static-content.springer.com10.1007/s00… · Web viewGene/variant/ID. Novelty. Clinical Synopsis On...