A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.

Journal Article (Journal Article)

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10-14). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.

Full Text

Duke Authors

Cited Authors

  • Schoch, K; Meng, L; Szelinger, S; Bearden, DR; Stray-Pedersen, A; Busk, OL; Stong, N; Liston, E; Cohn, RD; Scaglia, F; Rosenfeld, JA; Tarpinian, J; Skraban, CM; Deardorff, MA; Friedman, JN; Akdemir, ZC; Walley, N; Mikati, MA; Kranz, PG; Jasien, J; McConkie-Rosell, A; McDonald, M; Wechsler, SB; Freemark, M; Kansagra, S; Freedman, S; Bali, D; Millan, F; Bale, S; Nelson, SF; Lee, H; Dorrani, N; UCLA Clinical Genomics Center, ; Undiagnosed Diseases Network, ; Goldstein, DB; Xiao, R; Yang, Y; Posey, JE; Martinez-Agosto, JA; Lupski, JR; Wangler, MF; Shashi, V

Published Date

  • February 2, 2017

Published In

Volume / Issue

  • 100 / 2

Start / End Page

  • 343 - 351

PubMed ID

  • 28132692

Pubmed Central ID

  • PMC5294886

Electronic International Standard Serial Number (EISSN)

  • 1537-6605

Digital Object Identifier (DOI)

  • 10.1016/j.ajhg.2016.12.013


  • eng

Conference Location

  • United States