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Am J Hum Genet. 2017 Feb 2;100(2):343-351. doi: 10.1016/j.ajhg.2016.12.013. Epub 2017 Jan 26.

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

Collaborators (186)

Nelson SF, Grody WW, Lee H, Strom SP, Vilain E, Deignan J, Quintero-Rivera F, Kantarci S, Dorrani N, Mullegama S, Kang SH, Szelinger S, Alejandro ME, Bacino CA, Balasubramanyam A, Burrage LC, Clark GD, Craigen WJ, Dhar SU, Emrick LT, Graham BH, Hanchard NA, Jain M, Lalani SR, Lee BH, Lewis RA, Mashid AS, Moretti PM, Nicholas SK, Orange JS, Posey JE, Potocki L, Rosenfeld JA, Scott DA, Tran AA, Bellen HJ, Wangler MF, Yamamoto S, Eng CM, Muzny DM, Ward PA, Yang Y, Gropman AL, Goldstein DB, Stong N, Jiang YH, McConkie-Rosell A, Pena LDM, Schoch K, Shashi V, Spillmann RC, Sullivan JA, Walley NM, Beggs AH, Briere LC, Cooper CM, Donnell-Fink LA, Krieg EL, Krier JB, Lincoln SA, Loscalzo J, Maas RL, MacRae CA, Pallais JC, Rodan LH, Silverman EK, Stoler JM, Sweetser DA, Walsh CA, Esteves C, Holm IA, Kohane IS, Mazur P, McCray AT, Might M, Ramoni RB, Splinter K, Bick DP, Birch CL, Boone BE, Brown DM, Dorset DC, Handley LH, Jacob HJ, Jones AL, Lazar J, Levy SE, Newberry JS, Schroeder MC, Strong KA, Worthey EA, Dayal JG, Eckstein DJ, Gould SE, Howerton EM, Krasnewich DM, Loomis CR, Mamounas LA, Manolio TA, Mulvihill JJ, Wise AL, Soldatos AG, Brush M, Gourdine JF, Haendel M, Koeller DM, Kyle JE, Metz TO, Waters KM, Webb-Robertson BM, Ashley EA, Bernstein JA, Dries AM, Fisher PG, Kohler JN, Waggott DM, Wheeler MT, Zornio PA, Allard P, Barseghyan H, Dell'Angelica EC, Dipple KM, Dorrani N, Herzog MR, Lee H, Nelson SF, Palmer CGS, Papp JC, Sinsheimer JS, Vilain E, Adams CJ, Burke EA, Chao KR, Davids M, Draper DD, Estwick T, Frisby TS, Frost K, Gartner V, Godfrey RA, Goheen M, Golas GA, Gordon MGG, Groden CA, Hackbarth ME, Hardee I, Johnston JM, Koehler AE, Latham L, Latour YL, Lau CC, Levy DJ, Liebendorder AP, Macnamara EF, Maduro VV, Markello TC, McCarty AJ, Murphy JL, Nehrebecky ME, Novacic D, Pusey BN, Sadozai S, Schaffer KE, Sharma P, Thomas SP, Tolman NJ, Toro C, Valivullah ZM, Wahl CE, Warburton M, Weech AA, Yu G, Adams DR, Gahl WA, Malicdan MCV, Tifft CJ, Wolfe LA, Lee PR, Postlethwait JH, Westerfield M, Bican A, Hamid R, Newman JH, Phillips JA 3rd, Robertson AK, Cogan JD.

Author information

1
Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
3
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
4
Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, Rochester, NY 14627, USA.
5
Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Norwegian National Unit for Newborn Screening, Oslo University Hospital, 0424 Oslo, Norway.
6
Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway.
7
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
8
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
9
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
10
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
11
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
12
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
13
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
14
Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
15
Norwegian National Unit for Newborn Screening, Oslo University Hospital, 0424 Oslo, Norway.
16
Division of Pediatric Neurology, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
17
Division of Neuroradiology, Department of Radiology, Duke Health, Durham, NC 27710, USA.
18
Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA; Division of Cardiology, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
19
Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
20
Duke Eye Center, Duke Health, Durham, NC 27710, USA.
21
Department of Pathology, Duke Health, Durham, NC 27710, USA.
22
GeneDx, Gaithersburg, MD 20877, USA.
23
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
24
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
25
Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
26
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
27
Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
28
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
29
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: michael.wangler@bcm.edu.
30
Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA. Electronic address: vandana.shashi@duke.edu.

Abstract

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.

KEYWORDS:

NACC1; cataracts; developmental/intellectual disabilities; epilepsy; irritability; microcephaly; stereotypy; whole-exome sequencing

PMID:
28132692
PMCID:
PMC5294886
DOI:
10.1016/j.ajhg.2016.12.013
[Indexed for MEDLINE]
Free PMC Article

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