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

TitleA Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.
Publication TypeJournal Article
Year of Publication2017
AuthorsSchoch, 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, ZCoban, Walley, N, Mikati, MA, Kranz, PG, Jasien, J, McConkie-Rosell, A, McDonald, M, Wechsler, SBurns, Freemark, M, Kansagra, S, Freedman, S, Bali, D, Millan, F, Bale, S, Nelson, SF, Lee, H, Dorrani, N, Goldstein, DB, Xiao, R, Yang, Y, Posey, JE, Martinez-Agosto, JA, Lupski, JR, Wangler, MF, Shashi, V
Corporate AuthorsUCLA Clinical Genomics Center, Undiagnosed Diseases Network
JournalAm J Hum Genet
Date Published2017 Feb 02
KeywordsAlleles, Amino Acid Sequence, Brain, Cataract, Child, Child, Preschool, Female, Genetic Variation, Genome-Wide Association Study, Humans, Infant, Intellectual Disability, Magnetic Resonance Imaging, Male, Microcephaly, Mutation, Missense, Neoplasm Proteins, Pedigree, Phenotype, Repressor Proteins, Spasms, Infantile

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). 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.

Alternate JournalAm J Hum Genet
PubMed ID28132692
PubMed Central IDPMC5294886
Grant ListU01 HG007672 / HG / NHGRI NIH HHS / United States
P50 HD055784 / HD / NICHD NIH HHS / United States
U54 NS093793 / NS / NINDS NIH HHS / United States
R01 HG011795 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States

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