Table 1.
Clinical and genotypic details of 54 families (55 individuals) with de novo variants in our cohort.
| ID | Age | Gender | Genetic diagnosis attained by | Disorder (MIM) | Inheritance pattern | Gene and variant nomenclature | ACMG classification |
|---|---|---|---|---|---|---|---|
| Single nucleotide variants and indels | |||||||
| P1 | 8 M | Male | Trio ES | Intellectual developmental disorder, X-linked 93 (300659)a | XLR | BRWD3 (NM_153252.5): c.828_829dup p.(Lys277IlefsTer24) | Pathogenic |
| P2 | 7 Y | Female | Trio ES | Rett syndrome, congenital variant (613454) | AD | FOXG1 (NM_005249.5): c.602G>C p.(Arg201Pro) | Likely pathogenic |
| P3 | 3 Y | Male | Singleton ES | Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type (300534)a | XLR | KDM5C (NM_004187.5): c.3656T>G p.(Leu1219Arg) | Likely pathogenic |
| P4 | 14 Y | Male | Singleton ES | Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities (618505)a | AD | KDM6B (NM_001348716.2): c.1603G>A p.(Val535Met) | Likely pathogenic |
| P5 | 6 Y | Female | Singleton ES | Rubinstein-Taybi syndrome 1 (180849) | AD | CREBBP (NM_004380.3): c.1867_1874del p.(Asp623HisfsTer9) | Pathogenic |
| P6 | 2 Y | Female | Trio ES | Rett syndrome (312750) | XLD | MECP2 (NM_001110792.2): c.352C>T p.(Arg118Trp) | Pathogenic |
| P7 | 1 Y | Female | Trio ES | Intellectual developmental disorder, autosomal dominant 23 (615761)a | AD | SETD5 (NM_001080517.3): c.1967T>G p.(Leu656Ter) | Pathogenic |
| P8 | 12 Y | Female | Singleton ES | Ververi-Brady syndrome (617982)a | AD | QRICH1 (NM_198880.3): c.1585dup p.(Cys529LeufsTer13) | Pathogenic |
| P9 | 6 M | Male | Singleton ES | Cornelia de Lange syndrome 1 (122470) | AD | NIPBL (NM_133433.4): c.328A>T p.(Lys110Ter) | Pathogenic |
| P10 | 2 Y | Male | Mendeliome | Tuberous sclerosis-2 (613254) | AD | TSC2 (NM_000548.5): c.1096G>T p.(Glu366Ter) | Pathogenic |
| P11 | 3 M | Male | Singleton ES | Kabuki syndrome 1 (147920) | AD | KMT2D (NM_003482.4): c.6109G>C p.(Asp2037His) | Likely pathogenic |
| P12 | 1 Y | Female | Mendeliome | Lissencephaly, X-linked (300067)a | XL | DCX (NM_001195553.2): c.536C>A p.(Pro179His) | Likely pathogenic |
| P13 | 1 Y | Male | Singleton ES | Coffin-Siris syndrome 11 (618779) | AD | SMARCD1 (NM_003076.5): c.1432dup p.(Arg478ProfsTer3) | Pathogenic |
| P14 | 1 Y | Female | Trio ES | Bohring-Opitz syndrome (605039) | AD | ASXL1 (NM_015338.6): c.1435_1436del p.(Pro479ArgfsTer5) | Pathogenic |
| P15 | 2 Y | Male | Singleton ES | Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (615937) | AD | AKT3 (NM_005465.7): c.1393C>T p.(Arg465Trp) | Pathogenic |
| P16 | 3 Y | Male | Singleton ES | Contractural arachnodactyly, congenital (121050) | AD | FBN2 (NM_001999.4): c.3466T>C p.(Cys1156Arg) | Likely pathogenic |
| P17 | 1 Y 6 M | Female | Singleton ES | Craniosynostosis 3 (615314)a | AD | TCF12 (NM_207037.2): c.1807C>T p.(Arg603Trp) | Likely pathogenic |
| P18 | 1 Y 6 M | Female | Singleton ES | Neurodevelopmental disorder with absent language and variable seizures (618707)a | AD | WASF1 (NM_003931.3): c.1516C>T p.(Arg506Ter) | Pathogenic |
| P19 | 1 Y | Female | Mendeliome | BRAF-related disordera | AD | BRAF (NM_004333.5): c.1406G>A p.(Gly469Glu) | Pathogenic |
| P20 | 3 Y | Male | Singleton ES | Coffin-Siris syndrome, 4 (614609) | AD | SMARCA4 (NM_003072.5): c.3139A>C p.(Asn1047His) | Likely pathogenic |
| P21 | 5 Y | Male | Singleton ES | Mucopolysaccharidosis II (309900) | XLR | IDS (NM_000202.8): c.305T>C p.(Leu102Pro) | Likely pathogenic |
| P22 | 3 Y | Female | Singleton ES | Cortical dysplasia, complex, with other brain malformations 4 (615412)a | AD | TUBG1 (NM_001070.5): c.421A>C p.(Ile141Leu) | Likely pathogenic |
| P23 | 1 Y | Male | Singleton ES | Wiedemann-Steiner syndrome (605130) | AD | KMT2A (NM_001197104.2: c.5363+1G>A); NC_000011.10: g.118494768G>A | Pathogenic |
| P24 | 6 Y | Male | Singleton ES | Sotos syndrome (117550) | AD | NSD1 (NM_022455.5): c.3017del p.(Pro1006LeufsTer34) | Pathogenic |
| P25 | 5 Y | Female | Trio ES | Neurodevelopmental disorder with spastic diplegia and visual defects (615075)a | AD | CTNNB1 (NM_001904.4): c.1420C>T p.(Arg474Ter) | Pathogenic |
| P26 | 5 Y | Male | Trio ES | Intellectual developmental disorder, autosomal dominant 22 (612337)a | AD | ZBTB18 (NM_205768.3): c.1309C>T p.(His437Tyr) | Likely pathogenic |
| P27 | 2 Y | Male | TSS | Mucopolysaccharidosis II (309900) | XLR | IDS (NM_000202.8): c.708+2T>C | Pathogenic |
| P28 | 2 Y | Female | Singleton ES | Noonan syndrome 8 (615355) | AD | RIT1 (NM_006912.6): c.170C>G p.(Ala57Gly) | Pathogenic |
| P29 | 3 Y | Female | Trio ES | Wiedemann-Steiner syndrome (605130) | AD | KMT2A (NM_001197104.2): c.1837C>T p.(Arg613Ter) | Likely pathogenic |
| P30 | 6 Y | Male | Trio ES | Intellectual developmental disorder, autosomal dominant 62 (618793)a | AD | DLG4 (NM_001321075.3): c.1607C>T p.(Pro536Leu) | Likely pathogenic |
| P31 | 4 Y | Female | Trio ES | Cleft palate, cardiac defects, and intellectual disability (600987)a | AD | MEIS2 (NM_170675.5): c.973A>G p.(Asn325Asp) | Likely pathogenic |
| P32 | 1 Y | Male | Mendeliome | GAND syndrome (615074)a | AD | GATAD2B (NM_020699.4): c.535C>T p.(Arg179Ter) | Pathogenic |
| P33 | 8 Y | Male | Trio ES | Developmental delay, hypotonia, and impaired language (620012)a | AD | FBXW7 (NM_001349798.2): c.2065C>T p.(Arg689Trp) | Likely pathogenic |
| P34 | 5 Y | Female | Singleton ES | Dias-Logan syndrome (617101)a | AD | BCL11A (NM_022893.4): c.1486G>T p.(Glu496Ter) | Pathogenic |
| P35 | 2 Y | Male | Singleton ES | Rett syndrome, congenital variant (613454) | AD | FOXG1 (NM_005249.5): c.506del p.(Gly169AlafsTer23) | Pathogenic |
| P36 | 10 Y | Male | Mendeliome | Nicolaides-Baraitser syndrome (601358)a | AD | SMARCA2 (NM_003070.5): c.3485G>A p.(Arg1162His) | Likely pathogenic |
| P37 | 4 Y | Male | Singleton ES | KBG Syndrome (148050) | AD | ANKRD11 (NM_001256183.2): c.424C>T p.(Gln142Ter) | Pathogenic |
| P38 | 6 Y | Female | Trio ES | Wiedemann-Steiner syndrome (605130) | AD | KMT2A (NM_001197104.2): c.4643_4644insACTCCAGGCAAAGG p.(Trp1549Leufs*42) | Pathogenic |
| P39 | 4 Y | Male | Singleton ES | Coffin-Siris syndrome 1 (135900) | AD | ARID1B (NM_020732.3): c.3898C>T p.(Gln1300Ter) | Pathogenic |
| P40 | 1 Y | Female | Singleton ES | Cortical dysplasia, complex, with other brain malformations 13 (614563) | AD | DYNC1H1 (NM_001376.5): c.9751G>A p.(Glu3251Lys) | Likely pathogenic |
| P41 | 3 Y | Female | Singleton ES | Rett syndrome (312750) | XLD | MECP2 (NM_001110792.2): c.538C>T p.(Arg180Ter) | Pathogenic |
| P42 | 7 Y | Male | Singleton ES | Intellectual developmental disorder, autosomal dominant 43 (616977)a | AD | HIVEP2 (NM_006734.4): c.5890G>T p.(Gly1964Ter) | Pathogenic |
| P43 | 8 Y | Male | Singleton ES | Intellectual developmental disorder, X-linked 98 (300912) | XLR | NEXMIF (NM_001008537.3): c.1441C>T p.(Arg481Ter) | Pathogenic |
| P44 | 4 Y | Male | Singleton ES | Intellectual developmental disorder with seizures and language delay (619000)a | AD | SETD1B (NM_001353345.2): c.4241C>A p.(Ser1414Tyr) | Likely pathogenic |
| P45 | 1 Y | Female | Singleton ES | Intellectual developmental disorder, autosomal dominant 7 (614104)a | AD | DYRK1A (NM_001347721.2): c.658_659del p.(Met220ValfsTer10) | Pathogenic |
| P46 | 9 Y | Male | Singleton ES | Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (619595)a | AD | SRCAP (NM_006662.3): c.6127G>A p.(Gly2043Arg) | Likely pathogenic |
| P47 | 3 M | Male | TSS | PCWH syndrome (609136) | AD | SOX10 (NM_006941.4): c.1400A>T p.(Ter467LeuextTer86) | Likely pathogenic |
| P48 | 5 Y | Female | Singleton ES | Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (300749) | XLD | CASK (NM_001367721.1): c.1811del p.(Leu604CysfsTer14) | Pathogenic |
| P49 | 1 Y | Male | Singleton ES | MASA syndrome (303350)a | XLR | L1CAM (NM_001278116.2): c.649A>G p.(Arg217Gly) | Likely pathogenic |
| P50b | 9 M | Female | Singleton ES | Bainbridge-Ropers syndrome (615485)a | AD | ASXL3 (NM_030632.3): c.1429dup p.(Ser477PhefsTer2) | Pathogenic |
| P51b | 2 Y | Male | Singleton ES | Bainbridge-Ropers syndrome (615485)a | AD | ASXL3 (NM_030632.3): c.1429dup p.(Ser477PhefsTer2) | Pathogenic |
| P52 | 8 M | Female | Singleton ES | Noonan syndrome 3 (609942) | AD | KRAS (NM_004985.5): c.40G>A p.(Val14Ile) | Pathogenic |
| P53 | 3 Y | Male | Singleton ES | Rett syndrome, congenital variant (613454) | AD | FOXG1 (NM_005249.5): c.602G>C p.(Arg201Pro) | Likely pathogenic |
| Copy number variants | |||||||
| P54 | 1 day | Male | Singleton ES | Rubinstein-Taybi syndrome 1 (180849) | AD | CREBBP (NM_004380.3) 16p13.3 (3727580-3851110) x 1 | Pathogenic |
| P55 | 6 days | Female | Singleton ES | Polycystic kidney disease, infantile severe, with tuberous sclerosis (600273) | AD |
TSC2-PKD1 16p13.3 (2069904-2147985) x 1 |
Pathogenic |
Y Years, M months, ES exome sequencing, TSS Targeted Sanger sequencing, AD Autosomal dominant, XL X-linked, XLR X-linked recessive, XLD X-linked dominant.
aRare syndromes with ID not reported previously from Indian population.
bP50 and P51 are siblings harboring a de novo variant, c.1429dup p.(Ser477PhefsTer2) in ASXL3 (NM_030632.3) causing Bainbridge-Ropers syndrome (MIM #615485), suggesting the possibility of gonadal mosaicism in either of the phenotypically unaffected parents.