Background
Methods
Group A: Confirmed pathogenic (n = 12)
a
| |||
---|---|---|---|
Genes (Isoforms) | Variants (PMID) | Diagnoses (MIM) | Comments |
Autosomal Recessive Inheritance | |||
TALDO1 (NM_006755) | c.574C > T (p.A192C) (23315216) | Transaldolase deficiency (606003) | Elevated level of polyol in urine. Affected family members had the same variant. |
ETHE1 (NM_014297) | c.488G > A (p.R163Q) b(14732903) | EE (602473) | Urine organic acid and acylglycine profiles were consistent with ethylmalonic encepathopathy. |
FBXL4 c
| c.1304G > T (p.R435L) b(23993193) | MTDPS13(615471) | Affected sibling had the same variant and healthy siblings were negative. |
DGUOK (NM_080916) | c.763_765del (p.D255del) b
| MTDPS3 (251880) | Affected sibling had the same variant. |
PEX16 (NM_004813) | c.859C > T (p.R287C) b
| 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) | c.272G > C (p.C91S) b
| 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) | c.379C > G (p.L127V)b
| BRIC (243300) | Affected sibling had the same variant and healthy siblings were negative. |
MTPAP (NM_018109) | c.1468G > T (p.V490L) | 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) | c.205C>T (p.R69W) (16845400) | 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)]. |
Autosomal Dominant Inheritance | |||
FOXG1
|
c.1397G > A (p.G466E)
b
| Rett (613454) | Developmental regression, hypotonia, failure to thrive. |
ANK2 (NM_001148) |
c.1135C > T (p.R379C)
| 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) |
c.593G=/>A (p.G198D)
| EIEE2 (300672) | Global developmental delay and regression, intellectual disability, hypertonia, and seizure disorder. Parents were negative. |
Group B: Likely pathogenic (n = 12)
a
| |||
Autosomal Recessive Inheritance | |||
SLC4A4 (NM_000334) | c.2230G > A (p.A744T) | RTA, proximal (604278) | Severe RTA and ocular hypertension. Parents were heterozygous. |
G6PC (NM_000151) | c.352G > C (p.A118P) (24980439) | GSD1A (232200) | Hypoglycemia, hepatosplenomegaly, ↑lactate, left ventricular hypertrophy, and family history of cardiomyopathy. |
MPDZ (NM_003829) |
c.[394G>A]; [1744C>G]
p.[G132S); [L582V]
| HYC2 (615219) | Communicating hydrocephaly. |
TTN (NM_133378) |
c.[9160 G > C;68120 A > G]; [74633C > T] p.[E3054;Y22707C];[A24878V]
| 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) | c.1027A > G (p.K343E) | MIPEP (602241) | Developmental delay, hypotonia, dysmorphism, microcephaly, vision loss, and atrial septum defect. |
ALG9 (NM_024740) | c.694G > C (p.A232P) | 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) | c.1214G > A (p.R405Q) | 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) | c.154G > A (p.V52M) | 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)]. |
Autosomal Dominant Inheritance | |||
ABCB6 (NM_005689) |
c.[4G > A; 904C > G] p.[V2M;L302V]
| 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) |
c.3758 T > A (p.I1253N)
| 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) |
c.865G > A (p.V289M) (8872460) | 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) |
c.404A > G (p.Y135C)
| 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). |
Gene (Isoform) | Variants (PMID) | Diagnosis (MIM) | Comments |
---|---|---|---|
Mitochondrial inheritance | |||
tRNA Ala
| m.5591G > Ab (16476954) | MTTA (590000) | Failure to thrive, ptosis, myopathy, normal mitochondrial studies on muscle biopsy. |
ND5
| m.13513G > A (p.D393N)b (12509858) | MTND5 (516005) | Developmental regression, dysmorphic features, esotropia, chorioretinal atrophy, seizure, left ventricular hypertrophy, renal insufficiency, brain image suggestive of Leigh syndrome. |
X-Linked inheritance | |||
PDHA1 (NM_000284) |
c.787C > G (p.R263G) (1508605) | PDHAD (312170) | Brain image suggestive of Leigh syndrome; low complex II (succinate dehydrogenase) activity in the fibroblasts. Two heterozygous (‘cis’ configuration) novel missense variants, c.321C > G (p.1107 M) and c.338A > T (p.N113I), in SDHA were found in patient and father. |
Autosomal recessive inheritance | |||
FBXL4 (NM_012160) | c.1067delG (p.G356fs) (23993194) | MTDPS13 (615471) | Developmental regression, hypotonia, failure to thrive, microcephaly, lactic acidosis, normal fibroblast mitochondrial studies. Three siblings died in infancy. |
C10orf2 (NM_021830) | c.1198C > T (p.R400C) (21364701) | MTDPS7 (271245) | Developmental regression, hearing loss, scoliosis, reduced activities of complexes I & IV in myocytes; normal activities in fibroblasts. Two cousins with Leigh disease. |
MTHFR (NM_005957) | c.1596C > G(p.Y532) (a)
| MTHFRD (236250) | Progressive encephalopathy, seizure, cerebral venous thrombosis, gangrenous like bullous formation in the leg, congenital heart disease, ↑homocysteine, ↓methionine. |
PYCR2 (NM_013328) | c.28C > T(p.Q10X) (a)
| HLD10 (616420) | Developmental regression, failure to thrive, seizure, microcephaly, severe demyelination, thin corpus callosum. |
c.796C > T(p.R266X) (a)
| Developmental delay, hypotonia, failure to thrive, microcephaly, thin corpus callosum, delayed myelination. | ||
HEXA (NM_000520) | c.2 T > C | Tay-Sachs (268800) | Developmental regression, failure to thrive, seizure disorders, dystonia, feeding difficulties constipation. Diagnosis confirmed by enzyme analysis. |
HEXB (NM_000521) | c.826_829del (p.E276fs) | Sandhoff (268800) | Developmental regression, failure to thrive, feeding difficulties, seizure, and vision loss. |
SUMF1 (NM_182760) |
c.691dupT (p.W231fs) c.689A > G (p.E230ZG)
| MSD (272200) | Developmental delay, seizure, hepatomegaly, delayed myelination, ↑urine sulfatide, ↑urine heparan sulphate. |
UROC1 (NM_144639) | c.855G > A (p.W285X) (a)
| UROCD (276880) | Intellectual disabilities, attention deficit and hyperactivity disorder, hyperextensible joints, ↑imidazole propionate. |
TBX19 (NM_005149) | c.604-1G > C (a)
| IAD (201400) | Intellectual disabilities, congenital hypothyroidism, two sisters died in infancy with hypoglycemia. |
HSD3B7 (NM_025193) | c.45_46del (p.G17fs) (12679481) | CBAS1 (607765) | Neonatal cholestasis, hepatosplenomegaly, hypotonia, failure to thrive. |
Gene (Isoform) | Variants (PMID) | Diagnosis (MIM) | Comments |
---|---|---|---|
X-Linked Inheritance | |||
PAK3 (NM_002578) |
c.1279 T > C (p.Y427H)
| MRX30 (300558) | Intellectual disabilities, macrocephaly, obesity. |
Autosomal Dominant Inheritance | |||
BRAF (NM_004333) |
c.1914 T > G (p.D638E) (19206169) | CFC1 (115150) | Cortical blindness, seizures, stridor, constipation and developmental delay. |
DYNC1H1 (NM_001376) |
c.10973G > A (p.G3658E)
| MRD13 (614563) | Developmental regression, seizure, microcephaly, cataract, lissencephaly, pachygyria, grey matter heterotopia, hypoplasia of the corpus callosum. |
ARID1B (NM_020732) |
c.4870C > T (p.R1624X)
(a)
| Coffin-Siris (135900) | Mucopolysaccharidosis suspected clinically. |
ARID1B (NM_020732) |
c.3689 + 1G > C
| Coffin-Siris (135900) | Global developmental delay, failure to thrive, acute encephalopathy with hypoglycemia and metabolic acidosis. |
MYBPC3 (NM_000256) |
c.776delinsTT (p.A259fs)
| CMD1MM (615396) | Dilated cardiomyopathy. |
Autosomal Recessive Inheritance | |||
SNX10 (NM_001199835) | c.112-1G > C | OPTB8 (615085) | Central hypotonia, optic atrophy, osteopetrosis, pulmonary hypoplasia, hyperpigmented macules. |
TRAPPC11 (NM_199053) | c.2938G > A (p.G980R) (23830518) | LGMD2S (615356) | Developmental delay, head nodding, hypotonia, ↑CPK, ↑plasma phenylalanine, normal CSF neurotransmitters. Homozygous c.362 T > C (p.I121T) variant in COQ9 (normal muscle coenzyme Q10 activity). |
PCSK1 (NM_000439) | c.1312C > T (p.R438X) | Proprotein convertase 1/3 deficiency (600955) | Brain hemorrhage, congenital diarrhea. |
ERCC5 (NM_000123) | c.205C > T (p.R69X)(a)
| Cockayne (278780) | Hypotonia, developmental delay and seizure. Clinically suspected to have MLCD. |
AHI1 (NM_017651) | c.1051C > T (p.R351X) (15322546) | Joubert syndrome-3 (608629) | Intellectual disability, hypotonia, repetitive hand movements, brain atrophy. |
PRX (NM_181882) | c.1090C > T (p.R364X) (21741241) | Dejerine-Sottas (145900) | Abnormal gait, hearing loss, loss of dexterity in hands, scoliosis. |
TREX1 (NM_003629) | c.341G > A (p.R114H) (21270825) | RVCL (192315) | Cognitive impairment, hypotonia, joint contracture, glaucoma, brain atrophy, sibling died with the same features. |
DOK7 (NM_173660) |
c.1124_1127dup (p.A378fs) & c.1457dup (p.A487fs) (16917026) | Myasthenia, limb-girdle (254300) | Hypotonia, myopathic changes in proximal muscles. |
ADD3 (NM_016824) | c.1100G > A (p.G367D) (23836506) | Adducin-gamma (601568) | Developmental delay, central hypotonia and peripheral spasticity, cortical brain atrophy, delayed myelination of white matter. |
RECQL4 (NM_004260) | c.1000G > T (p.E334X)(a)
| RTS (268400) | Premature, intrauterine growth retardation, dry skin, clinically suspected to have MOPD2. |
IKBKB (NM_001556) | c.849G > A (p.W283X)(a)
| IMD15 (615592) | Failure to thrive, recurrent infections, two sibling died with the same presentation. |