Case# Subject 3-1, male, 11yo, Pakistani

CasePresentingHPOs HP:0000750, HP:0011342, HP:0000286, HP:0000431, HP:0000490, HP:0000717, HP:0007302, HP:0000218, HP:0001500, HP:0001837, HP:0002650, HP:0001249, HP:0001252, HP:0000717 (Speech delay, Mild global developmental delay, Epicanthus, Broad nasal bridge, Deep set eyes, Bipolar disorder, High palate, Broad fingers, Broad toes, Scoliosis, Intellectual Disability, Hypotonia, Autism)

HPOFreeText: mild speech/motor/cognitive delay, mild prominence of lateral ventricles, mild scoliosis, mild-moderate hypotonia

CaseNotHPOs HP:0002376, HP:0001250 (Developmental regression, Seizures)

NotHPOFreeText: Ventillator dependence

CasePreviousTesting Variants previously reported with a minor allele frequency > 1% were excluded. WES for additional compound-heterozygous, X-linked, or heterozygous de novo variants was negative.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES on all families, confirmed heterozygous/compound heterozygous with Sanger. Sanger on individuals with an affected family member. Parents confirmed heterozygous for childrens' variants

Variant NM_001163435.2:c.1652T>C(p.Leu551Pro), homozygous

ClinVar n/a

CAID CA357822100

gnomAD n/a

VariantEvidence n/a

CaseAddInfo consanguinity

CasePMIDs n/a

Case# Subject 1-1, male, 5yo died, Saudi

CasePresentingHPOs HP:0001558, HP:0000750, HP:0011344, HP:0002283, HP:0006829, HP:0001250, HP:0000340, HP:0000414, HP:0010804, HP:0000582, HP:0000496, HP:0002099, HP:0000964, HP:0001249 (Decreased fetal movement, Speech delay, Severe global developmental delay, Diffuse brain atrophy, Severe hypotonia, Seizures, Sloping forehead, Bulbous nose, Tented upper lip, Upslanted palpebral fissure, Abnormality of eye movement, Asthma, Eczema, Intellectual disability)

HPOFreeText: Oligohydramnios, Abnormal white matter signal intensity, Delayed reflexes

CaseNotHPOs HP:0002376 (Developmental regression)

NotHPOFreeText: Ventilator dependence

CasePreviousTesting Variants previously reported with a minor allele frequency > 1% were excluded. WES for additional compound-heterozygous, X-linked, or heterozygous de novo variants was negative. Included in previous study based on a neurogenetic diagnosis, positive family history, consanguineous parents, and no candidate genes identified by autozygosity mapping.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES on all families, confirmed heterozygous/compound heterozygous with Sanger. Sanger on individuals with an affected family member. Parents confirmed heterozygous for childrens' variants

Variant NM_033115.4(TBCK):c.1708+1G>A, homozygous

ClinVar 183338

gnomAD 0.00006693(European(Non-Finnish)), 0.00003244(total)

VariantEvidence (Fig 2A) Western blot: TBCK expression reduced in patient fibroblasts by 78%.

CaseAddInfo Consanguinity

CasePMIDs 25558065

Case# Subject 3-1, male, 11yo, Pakistani

CasePresentingHPOs HP:0000750, HP:0011342, HP:0000286, HP:0000431, HP:0000490, HP:0000717, HP:0007302, HP:0000218, HP:0001500, HP:0001837, HP:0002650, HP:0001249, HP:0001252, HP:0000717 (Speech delay, Mild global developmental delay, Epicanthus, Broad nasal bridge, Deep set eyes, Bipolar disorder, High palate, Broad fingers, Broad toes, Scoliosis, Intellectual Disability, Hypotonia, Autism)

HPOFreeText: mild speech/motor/cognitive delay, mild prominence of lateral ventricles, mild scoliosis, mild-moderate hypotonia

CaseNotHPOs HP:0002376, HP:0001250 (Developmental regression, Seizures)

NotHPOFreeText: Ventillator dependence

CasePreviousTesting Variants previously reported with a minor allele frequency > 1% were excluded. WES for additional compound-heterozygous, X-linked, or heterozygous de novo variants was negative.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES on all families, confirmed heterozygous/compound heterozygous with Sanger. Sanger on individuals with an affected family member. Parents confirmed heterozygous for childrens' variants

Variant NM_001163435.2:c.1652T>C(p.Leu551Pro), homozygous

ClinVar n/a

CAID CA357822100

gnomAD n/a

VariantEvidence n/a

CaseAddInfo consanguinity

CasePMIDs n/a

Case# Subject 1-1, male, 5yo died, Saudi

CasePresentingHPOs HP:0001558, HP:0000750, HP:0011344, HP:0002283, HP:0006829, HP:0001250, HP:0000340, HP:0000414, HP:0010804, HP:0000582, HP:0000496, HP:0002099, HP:0000964, HP:0001249 (Decreased fetal movement, Speech delay, Severe global developmental delay, Diffuse brain atrophy, Severe hypotonia, Seizures, Sloping forehead, Bulbous nose, Tented upper lip, Upslanted palpebral fissure, Abnormality of eye movement, Asthma, Eczema, Intellectual disability)

HPOFreeText: Oligohydramnios, Abnormal white matter signal intensity, Delayed reflexes

CaseNotHPOs HP:0002376 (Developmental regression)

NotHPOFreeText: Ventilator dependence

CasePreviousTesting Variants previously reported with a minor allele frequency > 1% were excluded. WES for additional compound-heterozygous, X-linked, or heterozygous de novo variants was negative. Included in previous study based on a neurogenetic diagnosis, positive family history, consanguineous parents, and no candidate genes identified by autozygosity mapping.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES on all families, confirmed heterozygous/compound heterozygous with Sanger. Sanger on individuals with an affected family member. Parents confirmed heterozygous for childrens' variants

Variant NM_033115.4(TBCK):c.1708+1G>A, homozygous

ClinVar 183338

gnomAD 0.00006693(European(Non-Finnish)), 0.00003244(total)

VariantEvidence (Fig 2A) Western blot: TBCK expression reduced in patient fibroblasts by 78%.

CaseAddInfo Consanguinity

CasePMIDs 25558065

Family#PresentingHPOs HP:0001252, HP:0000486, HP:0200006, HP:0001344, HP:0001249, HP:0010813 (Hypotonia, Strabismus, Slanting of palpebral fissure, Absent speech, Intellectual disability, Double crown)

HPOFreeText: narrowing of ventricles

FamilyNotHPOs n/a

NotHPOFreeText: n/a

CountryOrigin Northern Israel

Ethnicity Arab-Moslem

Race n/a

Family#PreviousTesting Excluded off-target, heterozygous, synonymous and X chromosome variants. Also excluded varaints that were called fewer than x8 with MAF > 1% in ExAC. Metabolic analyses as well as muscle biopsy had normal results.

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod WES confirmed with Sanger

Affected 2

Unaffected 2

Segregations 2

PublishedLOD n/a

eLOD n/a

AddSegregationInfo consanguineous

ProbandLabel Proband 2, male, 11yo diagnosis

CasePresentingHPOs HP:0000961, HP:0002098, HP:0006829, HP:0000237, HP:0000238, HP:0002079, HP:0000463, HP:0000218, HP:0000817, HP:0001250, HP:0000648, HP:0100702, HP:0000268, HP:0000338, HP:0000494, HP:0000520, HP:0002711, HP:0009092, HP:0000356, HP:0010864, HP:0002015, HP:0006532, HP:0001639, HP:0000276 (Cyanosis, Respiratory distress, Severe Hypotonia, Small anterior fontanelle, Hydrocephalus, Thin corpus callosum, Anteverted nares, High palate, Poor eye contact, Seizures, Optic nerve atrophy, Arachnoid cyst, Dolichocephaly, Hypomimic face, Downslanting palpebral fissures, Proptosis, Deep tongue groove, Gum ridge hypertrophy, Outer ear abnormality, Severe intellectual disability, Swallowing difficulties, Hypertrophic cardiomyopathy, Long face)

HPOFreeText: Neonatal cyanosis, no cry, respiratory distress, upper body hypotonia, small anterior fontanelle, lateral ventricle dilation, hydrocephalus, severe head lag, hypertrophic cardiomyopathy, thin corpus callosum, central hypotonia, anteverted nares, high palate, strabismus, and no eye contact. Convulsions, retro-cochlear defect-no response on left (2y), no expressive speech, partial atrophy of optic nerve and arachnoid cyst(5y), dolicocephaly, double crown, long face, decreased facial movement, downslanting palpebral fissures, mildly prominent eyes, deep grooves in tongue, gum hypertrophy, large simple auricles, small palms(7y). Diagnosis of severe ID, severe hypotonia, convulsions, swallowing abnormalities, recurrent pneumonia, small heart muscle fibers and primitive sarcomere structure at 11 years old.

CaseNotHPOs HP:0001507 (Growth abnormality)

NotHPOFreeText: n/a

Variant NM_001163435.2:c.1854del(p.Pro619GlnfsTer?)

ClinVar n/a

CAID CA658820911

gnomAD n/a

FamilyAddInfo variant absent in ~60,000 exomed individuals in Exac and in ~800 Moslem-Arab analyses. Affected sister who additionally presented with severe scoliosis, osteoporosis, narrow forehead, upslanted palpebral fissures, bushy eyebrows, flattened nose, porencephalic cyst, opistotonus, spenomegaly, prominent metopic suture and narrow high palate.

FamilyPMIDs n/a

Family#PresentingHPOs HP:0001252, HP:0000486, HP:0200006, HP:0001344, HP:0001249, HP:0010813 (Hypotonia, Strabismus, Slanting of palpebral fissure, Absent speech, Intellectual disability, Double crown)

HPOFreeText: narrowing of ventricles

FamilyNotHPOs n/a

NotHPOFreeText: n/a

CountryOrigin Northern Israel

Ethnicity Arab-Moslem

Race n/a

Family#PreviousTesting Excluded off-target, heterozygous, synonymous and X chromosome variants. Also excluded varaints that were called fewer than x8 with MAF > 1% in ExAC. Metabolic analyses as well as muscle biopsy had normal results.

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod WES confirmed with Sanger

Affected 2

Unaffected 2

Segregations 2

PublishedLOD n/a

eLOD n/a

AddSegregationInfo consanguineous

ProbandLabel Proband 2, male, 11yo diagnosis

CasePresentingHPOs HP:0000961, HP:0002098, HP:0006829, HP:0000237, HP:0000238, HP:0002079, HP:0000463, HP:0000218, HP:0000817, HP:0001250, HP:0000648, HP:0100702, HP:0000268, HP:0000338, HP:0000494, HP:0000520, HP:0002711, HP:0009092, HP:0000356, HP:0010864, HP:0002015, HP:0006532, HP:0001639, HP:0000276 (Cyanosis, Respiratory distress, Severe Hypotonia, Small anterior fontanelle, Hydrocephalus, Thin corpus callosum, Anteverted nares, High palate, Poor eye contact, Seizures, Optic nerve atrophy, Arachnoid cyst, Dolichocephaly, Hypomimic face, Downslanting palpebral fissures, Proptosis, Deep tongue groove, Gum ridge hypertrophy, Outer ear abnormality, Severe intellectual disability, Swallowing difficulties, Hypertrophic cardiomyopathy, Long face)

HPOFreeText: Neonatal cyanosis, no cry, respiratory distress, upper body hypotonia, small anterior fontanelle, lateral ventricle dilation, hydrocephalus, severe head lag, hypertrophic cardiomyopathy, thin corpus callosum, central hypotonia, anteverted nares, high palate, strabismus, and no eye contact. Convulsions, retro-cochlear defect-no response on left (2y), no expressive speech, partial atrophy of optic nerve and arachnoid cyst(5y), dolicocephaly, double crown, long face, decreased facial movement, downslanting palpebral fissures, mildly prominent eyes, deep grooves in tongue, gum hypertrophy, large simple auricles, small palms(7y). Diagnosis of severe ID, severe hypotonia, convulsions, swallowing abnormalities, recurrent pneumonia, small heart muscle fibers and primitive sarcomere structure at 11 years old.

CaseNotHPOs HP:0001507 (Growth abnormality)

NotHPOFreeText: n/a

Variant NM_001163435.2:c.1854del(p.Pro619GlnfsTer?)

ClinVar n/a

CAID CA658820911

gnomAD n/a

FamilyAddInfo variant absent in ~60,000 exomed individuals in Exac and in ~800 Moslem-Arab analyses. Affected sister who additionally presented with severe scoliosis, osteoporosis, narrow forehead, upslanted palpebral fissures, bushy eyebrows, flattened nose, porencephalic cyst, opistotonus, spenomegaly, prominent metopic suture and narrow high palate.

FamilyPMIDs n/a