Case# F1_IV:5, M, 6.5yo report, Saudi Arabia

CasePresentingHPOs HP:0001263, HP:0008947, HP:0001257, HP:0000486, HP:0000639, HP:0004326, HP:0000252

HPOcont: Global developmental delay, Infantile muscular hypotonia, Spasticity, Strabismus, Nystagmus, Cachexia, Microcephaly

Free text: "At 4.5 years of age, he was cachectic with a weight of 8.1 kg (−5.2 SD), short with a length of 89 cm (−3.7 SD), and microcephalic with a head circumference of 46 cm (−3.2 SD). He was inattentive and had no visual tracking ability as well as bilateral strabismus and nystagmus. He had severe axial hypotonia and appendicular hypertonia with spasticity."

CaseNotHPOs HP:0001250

NotHPOcont: Seizures

CasePreviousTesting "Plasma lactate, ammonia, uric acid, lipid profile, tandem mass spectrometry (MS), urine organic acids, plasma amino acids, and congenital disorder of glycosylation screenings did not reveal any abnormality. Chromosomal analysis and microarray were unremarkable. Glycosaminoglycans and oligosaccharides in the urine were normal. Lysosomal enzyme analysis was unremarkable. HEXB and SMN1 mutation analysis did not reveal pathogenic mutations. Brain MRI showed mild diffuse brain atrophy, and MRS (magnetic resonance spectroscopy) showed a mild reduction of the N-acetylaspartate peak but a normal lactate peak. Skeletal survey showed diffuse osteopenia."

CaseMethod1 Exome sequencing

CaseMethod2 Sanger

CaseGenotypingMethod autozygome filtering after exome sequencing, confirmed with sanger

Variant NM_032504.1(UNC80):c.3793C>T (p.Arg1265Ter)

ClinVar 219188

gnomAD 0.00004175(Latino), 0.000006613(Overall)

CaseAddInfo His first-cousin parents had two sons who died at 4 and 6 years of age with a reportedly identical phenotype of profound static encephalopathy and no seizures. The index individual has two living brothers and two sisters who are all healthy

Family#PresentingHPOs HP:0001290, HP:0001508, HP:0001263

HPOcont: Hypotonia, Failure to thrive, Global developmental delay

FamilyNotHPOs HP:0000486, HP:0000639, HP:0004326, HP:0000252, HP:0002353

NotHPOcont: Strabismus, Nystagmus, Cachexia, Microcephaly, EEG abnormality

CountryOrigin Saudi Arabia

Family#PreviousTesting Brain MRI showed normal parenchyma asnd myelination in F2 individuals, mild diffuse brain atrophy in F1_IV:5

Family#Method1 Sanger

Family#GenotypingMethod Exome sequencing on "one of the three affected members" then confirmed in remaining members with Sanger

Affected 3

Unaffected 7

PublishedLOD 4.7 (Combined with Family 1)

AddSegregationInfo consanguinity

ProbandLabel F1_IV:5

CasePresentingHPOs HP:0001263, HP:0001508, HP:0001290

HPOcont: Global developmental delay, Failure to thrive, Hypotonia

CaseNotHPOs HP:0001250

NotHPOcount: Seizures

Variant NM_032504.1(UNC80):c.3793C>T (p.Arg1265Ter)

ClinVar 219188

gnomAD 0.00004175(Latino), 0.000006613(Overall)

Case# ObeidIndex, F, 13yo report, Palestinian-Emirati

CasePresentingHPOs HP:0006829, HP:0010864, HP:0001263, HP:0000252, HP:0001344, HP:0001250, HP:0002650, HP:0000574, HP:0000414, HP:0000179, HP:0000307, HP:0000218, HP:0040079, HP:0030787, HP:0002136, HP:0001344

HPOcont: Severe muscular hypotonia, Severe intellectual disability, Global developmental delay, Microcephaly, Absent speech, Seizures, Scoliosis, Thick eyebrow, Bulbous nose, Thick lower lip vermilion, Pointed chin, High palate, Irregular dentition, Cerumen abnormality, Broad-based gait, Absent speech

Free Text: "birth weight of 2.6 Kg (< 10th centile), head circumference of 33 cm (< 3rd centile). At the age of 8 months, her developmental delay was noticed as she was unable to sit unsupported. Formally evaluated at one year of age, at which point EEG was suggestive of symptomatic localization-related epilepsy. EEG revealed ill-defined low spikes over the left temporooccipital area, suggesting symptomatic partial epilepsy. At age 11 developed subtle facial dysmorphic features, including bushy eyebrows, bulbous nose, anteverted nostrils, thick lower lip, pointed chin, high arched palate, irregular teeth, and waxy ears. As an eleven years and three months old girl, she is able to sit independently, without support. However, she has difficulty in standing from squat position. She can ambulate independently with a wide based gait with hands on flexion position, but is not able to run, jump, or pedal tricycle. She can climb stairs, but with support. She demonstrated a pincer grasp. She can do purposeful movements; as in the ability to reach, hold and transfer objects, and she can bring food to mouth. She can also dress herself with help, but does not zip or button. She does not have any meaningful speech, but babbles socially."

CaseNotHPOs HP:0002540, HP:0002019, HP:0011968, HP:0002014

NotHPOcont: Inability to walk, Constipation, Feeding difficulties, Diarrhea

CasePreviousTesting Brain MRI, thyroid function tests, metabolic screening, and eye examination were normal; as were the following genetic investigations: chromosomal microarray, karyotyping, FISH for 15q11–13 deletion, subtelomeric FISH, methylation analysis for Angelmann, and molecular analysis for UBE3A gene. "A 186 such variants were looked at individually in order to uncover any connections with the patient’s phenotype in the context of various modes of inheritance in the analyzed trio. For example, heterozygous mutations in NDRG4, RELN, TYRP1, REEP6, FABP2 and others were found and given low priority when looked at in the light of the patient’s phenotype. None of the other variants from that list appeared to have enough functional links to the patient’s condition to merit discussing it along with the UNC80 variant."

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmed with Sanger sequencing in trio

Variant NM_032504.1:c.8525G>A (p.Arg2842Gln)

CAID CA350413877

gnomAD 0.00006667(European (Non-Finnish), 0.00003230(Overall)

CaseAddInfo parental consanguinity, confirmed in trans

Case# Patient2, F, 5yo report, Chinese

CasePresentingHPOs HP:0000325, HP:0002007, HP:0000347, HP:0008897, HP:0001508, HP:0001249, HP:0000750, HP:0001270, HP:0008947, HP:0002360

HPOcont: Triangular face, Frontal bossing, Micrognathia, Postnatal growth retardation, Failure to thrive, Intellectual disability, Delayed speech and language development, Motor delay, Infantile muscular hypotonia, Sleep disturbance

Free Text: "The patient was referred for DD and failure to thrive without feeding difficulty at approximately three years of age. She could speak only simple words such as “baba” and “mama” and could not walk. A physical examination revealed hypotonia. Her head circumference was 44 cm (−3.7 SD). Her facial dysmorphisms included a triangular face; light, sparse hair; frontal bossing; strabismus; a thin upper lip; and micrognathia. At the age of five, she could stand with support but remained unable to ambulate or speak. She suffered from sleep disturbance and a tendency toward self-injury behaviors, such as hitting her head with her hands or bumping her head. Follow-up when the patient was 5 years and 9 months old showed that she could not walk or speak. At that time, her body length was 100 cm (−3.4 SD), and she weighed 11 kg (−4 SD)."

CaseNotHPOs HP:0000494, HP:0000369, HP:0002353, HP:0000358, HP:0000431, HP:0000319, HP:0012299, HP:0001182, HP:0001511, HP:0001250, HP:0002650, HP:0011968, HP:0002019

NotHPOcont: Downslanted palpebral fissures, Low-set ears, EEG abnormality, Posteriorly rotated ears, Wide nasal bridge, Smooth philtrum, Long distal phalanx of finger, Tapered finger, Intrauterine growth retardation, Seizures, Scoliosis, Feeding difficulties, Constipation

CasePreviousTesting Echocardiographic examination, brain magnetic resonance imaging (MRI) and an EEG revealed no abnormalities. Metabolic screening and assessments of the patient's thyroid function at age three produced normal results.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES, confirmed with Sanger

Variant (1) NM_032504.1:c.3719G>A (p.Trp1240Ter ), (2) NM_032504.1:c.4926_4937del (p.Asn1643_Leu1646del)

CAID (1) CA350741683 (2) CA658820715

CaseAddInfo nonconsanguineous parents, no parent testing mentioned, "younger brother presented similar phenotypes such as hypotonia and developmental delay. He died at the age of one year due to severe pneumonia. He was diagnosed as IHPRF2 clinically. However, no genetic analysis was performed, as DNA was unavailable."

Case# Patient1, Male, 1 week onset, Chinese

CasePresentingHPOs HP:0002007, HP:0000319, HP:0012299, HP:0001249, HP:0000750, HP:0001270, HP:0008947, HP:0001250, HP:0002019, HP:0002353, HP:0010804, HP:0000486

HPOcont: Frontal bossing, Smooth philtrum, Long distal phalanx of finger, Intellectual disability, Delayed speech and language development, Motor delay, Infantile muscular hypotonia, Seizures, Constipation, EEG abnormality, Tented upper lip vermilion, Strabismus

Free Text: "He experienced physiologic jaundice one week after birth. Hypotonia and psychomotor retardation were observed. He could raise his head at the age of one year and sit by himself when he was two years of age; he ambulated when he was three years old. At approximately five years of age, he could use only simple speech. He also exhibited poor balance and displayed hyperactive behavior and a happy and excitable disposition with frequent smiling and laughing. In addition, he suffered from constipation. Seizures occurred when he was two years old and were effectively treated with valproate and levetiracetam. When he was referred to our clinic at 6 years and 5 months of age, his height and weight were 120 cm (0 SD) and 20 kg (0 SD), respectively. When followed up at the age of 9.5 years, his height, weight and head circumference were 135 cm (−0.5 SD), 25 kg (−1.3 SD) and 51 cm (−0.5 SD), respectively. His facial features included frontal bossing, strabismus, a tented upper lip, a broad nasal bridge, and a short, smooth philtrum. He had long, slender fingers. An electroencephalograph (EEG) revealed excessively slow background."

CaseNotHPOs HP:0000494, HP:0000325, HP:0000369, HP:0000358, HP:0000431, HP:0000347, HP:0001182, HP:0001511, HP:0008897, HP:0001508, HP:0002650, HP:0011968, HP:0002360

NotHPOcont: Downslanted palpebral fissures, Triangular face, Low-set ears, Posteriorly rotated ears, Wide nasal bridge, Micrognathia, Tapered finger, Intrauterine growth retardation, Postnatal growth retardation, Failure to thrive, Scoliosis, Feeding difficulties, Sleep disturbance ,

CasePreviousTesting "methylation-specific multiplex ligation-dependent probe amplification revealed no abnormalities in the 15q11-q13 region. Chromosomal microarray tests also showed no pathogenic copy number variations."

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES, confirmed with Sanger

Variant (1) NM_032504.1(UNC80):c.4963C>T (p.Arg1655Cys), (2) NM_032504.1:c.8385C>G (p.Tyr2795Ter)

ClinVar (1) 545035

CAID (2) CA350413549

CaseAddInfo nonconsanguineous, parent testing not mentioned

PMID 19535918 Gene: UNC80

PMID: 28708303 Gene: UNC80

PMID 19092807 Gene: UNC80

Case# II-1, F, 13yo diagnosis, European

CasePresentingHPOs HP:0001254, HP:0001137, HP:0025404, HP:0008936, HP:0002509, HP:0025430, HP:0003739, HP:0002353, HP:0001508, HP:0000297, HP:0010804, HP:0000218, HP:0000347, HP:0001212, HP:0001864, HP:0040082, HP:0012167, HP:0030820, HP:0000276, HP:0000268, HP:0000549, HP:0000678, HP:0012166, HP:0002465

HPOcont: Lethargy, Alternating esotropia, Abnormal visual fixation, Muscular hypotonia of the trunk, Limb hypertonia, High-pitched cry, Myoclonic spasms, EEG abnormality, Failure to thrive, Facial hypotonia, Tented upper lip vermilion, High palate, Micrognathia, Prominent fingertip pads, Clinodactyly of the 5th toe, Happy demeanor, Hair-pulling, Hooded eyelid, Long face, Dolichocephaly, Abnormal conjugate eye movement, Skin-picking, Poor speech

Free Text: "Birth weight, length and head circumference were 3.149 kg (−0.18SD), 51 cm (+0.99SD), and 33 cm (−0.74SD), respectively. Although she did not cry immediately and was described as sleepy and lethargic, her Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. She has had poor weight gain throughout life. By 2 months of age, she developed alternating esotropia, poor visual fixation, truncal hypotonia, upper and lower extremity hypertonia and a high-pitched cry. She also had myoclonic jerks and jerky movements of her extremities. Her weight, height and head circumference were 4.6 kg (−1.57SD), 51 cm (−3.81 SD) and 39.2 cm (+0.06SD), respectively. A head CT scan detected no anatomical anomalies. An EEG showed excessively slow background without epileptiform activity. Despite intervention, her weight gain continued to fall off, and she was diagnosed with failure to thrive. She rolled over at age 6 months, sat unsupported at 1 year. A follow-up EEG at 14 months showed a slow dysrhythmic background compatible with a seizure predisposition and diffuse cerebral dysfunction. A brain MRI at 18 months of age showed normal anatomy and myelination. In the ensuing months, she demonstrated a happy disposition, low truncal muscle tone and distal hypertonia as well as a myopathic facial appearance, a tented upper lip, a high arched palate, micrognathia, prominent finger pads and mild fifth toe clinodactyly. At age 4 years and 1 month, a developmental assessment defined her overall functioning at no more than a 12-month-old equivalent; she was not autistic. At age 6 years and 11 months, she manifested sparse hair (trichotillomania), hooded eyelids, high arched palate, thin long face and mild micrognathia. At age 12 years, she walked with the support of splints. Her height, weight and head circumference were 127 cm (−3.64 SD), 22.6 kg (−4.06 SD), and 52 cm (−0.94SD), respectively. Her features included dolicocephaly, hooded eyelids, intermittently disconjugate gaze, sparse hair, high palate and crowded dentition. Developmental assessment documented behavioral difficulties including repetitive and self-stimulatory behaviors, sensory issues such as repetitively rubbing her hands on the floor and/or licking them and mouthing objects, rigidity, communication deficits, difficulties with emotional regulation and aggression when frustrated. Her aggression included the self-injurious behaviors of dermatillomania, biting and trichotillomania. She communicated with a few words, signs, gestures and a picture exchange communication system (PECS). She developed menses at age 13 years."

CasePreviousTesting "Family history was negative for intellectual disability, multiple congenital anomalies and recurrent miscarriages. Normal genetic investigations included a karyotype (550 band resolution), subtelomeric FISH, methylation studies of SNRPN, sequence analysis of UBE3A, and DMPK repeat analysis. Normal metabolic tests included transferrin isoelectric focussing, CSF amino acids and neurotransmitters, plasma amino acids, urine organic acids, urine purines and pyrimidines, serum acylcarnitines, blood ammonia and blood lactate. She also had normal audiological testing."

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod SNP array and WES, confirmed with Sanger qt/rtPCR

Variant (1) NM_032504.1:c.3983-3_3994delinsA (p.Ser1328Argfs19), (2) NM_032504.1:c.2431C>T (p.Arg811)

CAID (1) CA658820714, (2) CA350137388

VariantEvidence skin fibroblasts from affected sister showed no unc80 mRNA.

CaseAddInfo nonconsanguineous, confirmed in trans. Affected sister with similar phenotypes died of respiratory distress at age 7.