NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism

Abstract

NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n ¼ 8), transmitted (n ¼ 6), or inheritance unknown (n ¼ 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.

Molecular Dysregulation in Autism Spectrum Disorder

“…Candidate genes which have been the focus of ASD are: CACNAIC , GABAA receptor subunit , FOXP2 , HOXA1 , HOXB1 , HTR2A , MTHFR , RELN , RAY1/ST7 , IMMP2L , SLC6A4 , OXTR , UBE3A and WNT-2 [ 26 , 27 , 28 , 29 , 30 , 31 ]. More recently, a role for de novo deleterious NCKAP1 variants was reported in neurodevelopmental delay/autism, as variants can affect the neuronal migration in early cortical development [ 32 ]. POU3F2 , was identified as ASD risk gene, and it is a key transcription factor involved in neuronal differentiation, whose downstream target genes are strongly enriched for known ASD genes and mutations [ 33 ].…”

Routine Diagnostics Confirm Novel Neurodevelopmental Disorders

“…A possible association between NCKAP1 (HGNC:7666) and intellectual disability has already been proposed in 2017, while subsequent studies have further supplemented evidence for this gene–disease association through the collection of larger cohorts [ 9 , 10 , 11 , 12 ]. However, until now, there has been no OMIM association between NCKAP1 and the phenotypes of intellectual disability and autism, as proposed by the abovementioned studies.…”

Bioinformatics and next generation sequencing data analysis to identify key genes and pathways influencing in Parkinson’s disease

“…Signaling by NTRK1 (TRKA) [55], cardiac conduction [56], signaling by GPCR [57], immune system [58], cytokine signaling in immune system [59], interferon signaling [60] and toll-like receptor cascades [61] were responsible for development of PD. Recent studies have shown that EGR2 [62], WNT1 [63], ARC (activity regulated cytoskeleton associated protein) [64], CHRNA7 [65], SEZ6L2 [66], IL1RAPL2 [67], PER2 [68], PCDH19 [69], CNTNAP2 [70], SLC12A5 [71], CDK5 [72], ACTL6B [73], GABRD (gamma-aminobutyric acid type A receptor subunit delta) [74], CACNA1G [75], HTR2C [76], STX1A [77], ATP1A3 [78], RIMS3 [79], CNTNAP2 [80], CDH8 [81], SCAMP5 [82], SYNGR1 [83], ARHGEF9 [84], DLG3 [85], RBP4 [86], IL9 [87], S100A9 [88], HGF (hepatocyte growth factor) [89], C3 [90], FKBP5 [91], GABRE (gamma-aminobutyric acid type A receptor subunit epsilon) [92], NCKAP1L [93], PIK3CG [94], ITGB3 [95], ANXA1 [96], SYNE2 [97] and DBI (diazepam binding inhibitor, acyl-CoA binding protein) [98] were closely involved with the occurrence, development, and prognosis of autism spectrum disorder. EGR2 [99], ADCYAP1 [100], CHRNA7 [101], NRN1 [102], ETV5 [103], STXBP1 [104], CAMKK2 [105], VAMP2 [106], SYNGR1 [107], NOD2 [108], TLR2 [109], BRCA2 [110] and LEF1 [111] were previously reported to be critical for the development of bipolar disorder.…”