PMID 19092807 Gene: UNC80

PMID 19092807 Gene: UNC80

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)

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# 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.

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.