Table 1 Variants of unknown significance, which were confirmed pathogenic or likely pathogenic

TALDO1 (NM_006755)

Transaldolase deficiency (606003)

Elevated level of polyol in urine. Affected family members had the same variant.

ETHE1 (NM_014297)

EE (602473)

Urine organic acid and acylglycine profiles were consistent with ethylmalonic encepathopathy.

FBXL4 c

MTDPS13(615471)

Affected sibling had the same variant and healthy siblings were negative.

DGUOK (NM_080916)

MTDPS3 (251880)

Affected sibling had the same variant.

PEX16 (NM_004813)

PBD8B (614877)

Elevated level of very long chain fatty acids, low C26 beta-oxidation in plasma and fibroblasts. Fibroblasts showed enlarged peroxisomes. Affected sibling had the same variant.

HEXB (NM_000521)

Sandhoff disease (268800)

Low serum hexosaminidase activity. A pathologic variant in MCCC2 [c.1015G > A (p.V339M)] was also found, but urine organic acids were normal (PMID: 11181649).

ATP8B1 (NM_005603)

BRIC (243300)

Affected sibling had the same variant and healthy siblings were negative.

MTPAP (NM_018109)

SPAX4 (613672)

Developmental delay and regression at 8 months of age, central hypotonia, short stature, failure to thrive, cerebellar atrophy, absence-like episodes, and hip dislocation. Affected sibling had the same variant. Parents were heterozygous.

RNASEH2C (NM_032193)

AGS3 (610329)

Global developmental delay, central hypotonia, peripheral hypertonia, opisthotonus, microcephaly, failure to thrive, diffuse white matter hyperintensity, cortical brain atrophy, and dilated ventricles. WES also reported homozygous variant in CDK5RAP2 [c.412G > A (p.G138S); an unaffected sibling was homozygous for the same variant] and pathogenic heterozygous mutation in BUB1B [c.2441G > A (p.R814H)].

FOXG1

Rett (613454)

Developmental regression, hypotonia, failure to thrive.

ANK2 (NM_001148)

Long QT (600919)

Two siblings died of cardiac arrest; affected sibling had the same variant. Parents were heterozygous, but their phenotype was not investigated.

X-Linked Inheritance

CDKL5 (NM_003159)

EIEE2 (300672)

Global developmental delay and regression, intellectual disability, hypertonia, and seizure disorder. Parents were negative.

SLC4A4 (NM_000334)

RTA, proximal (604278)

Severe RTA and ocular hypertension. Parents were heterozygous.

G6PC (NM_000151)

GSD1A (232200)

Hypoglycemia, hepatosplenomegaly, ↑lactate, left ventricular hypertrophy, and family history of cardiomyopathy.

MPDZ (NM_003829)

HYC2 (615219)

Communicating hydrocephaly.

TTN (NM_133378)

CMD1G (604145

Mother was asymptomatic with the heterozygous c.9160 G > C and c.68120 A > G. Father was heterozygous for c.74633C > T.

MIPEP (NM_005932)

MIPEP (602241)

Developmental delay, hypotonia, dysmorphism, microcephaly, vision loss, and atrial septum defect.

ALG9 (NM_024740)

CDG1L (608776)

Patient had global developmental delay and regression, central and peripheral hypertonia, seizures, macrocephaly, brain atrophy, thin corpus callosum, and cysts in the white matter. WES also reported homozygous variants in NDUFV3 [c.552dup (p.L185fs)] and in KANK1 [c.1079G > A (p.S360N)].

GLRA1 (NM_000171)

HKPX1 (149400)

Global developmental delay, hypotonia then hypertonia, seizures, repetitive hand movements, startle reflex to tactile and sound, dysmorphic features (elongated face, big prominent ears), tall habitus, squint, scoliosis, and precious puberty. WES also reported homozygous variants in TTC37 [c.1828A > G (p.S610G)] and in CHD8 [c.1952G > A (p.R651Q)].

PLA2G6 (UC003aux.1)

NBIA2B (610217)

Developmental regression, hypertonia, failure to thrive, scoliosis, and skin anomalies. Brain MRI findings were consistent with NBIA2B. Cousin with spina bifida and hydrocephalus. WES also reported homozygous variant in ACOX1 [c.1165A > G (p.I1389V)] and compound heterozygous variant in SACS [c.2143C > A (p.P715T) and c.5732C > A (p.T1911M)].

ABCB6 (NM_005689)

MCOPCB7 (614497)

Autism, subtle microphthalmia, and repetitive hand movements. WES also identified a heterozygous variant in CHD7 [c.5689G > A (p.E1897K)]. (CHARGE, MIM: 214800) Father had small eyes and was heterozygous for both changes.

ITPR1 (NM_002222)

SCA15 (606658)

Ataxia and cerebellar atrophy without deafness. WES also reported a variant in MYH14 [c.1126G > T (p.G376C)]. (PMID: 15015131, MIM: 600652)

CHRNB1 (NM_000747)

CMS2A (616313)

Delayed motor milestone, hypotonia, pulmonary hypertension, seizures, and autistic features. Nerve conductive study was normal. Father had paranoid schizophrenia. This variant was previously reported (PMID:8872460).

KIF5C (NM_004522)

Cortical dysplasia, complex, with other brain malformations 2 (615282)

The disease is autosomal dominant. All family members were negative for the variant. WES also reported a variant in NRXN1 [c.1835A > G (p.D612G)]. Parents and one sibling were heterozygous (MIM: 614325).