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

  • Am J Hum Genet. 2017 Feb 2;100(2):343-351. doi: 10.1016/j.ajhg.2016.12.013.
Kelly Schoch  1 ,  Linyan Meng  2 ,  Szabolcs Szelinger  3 ,  David R Bearden  4 ,  Asbjorg Stray-Pedersen  5 ,  Oyvind L Busk  6 ,  Nicholas Stong  7 ,  Eriskay Liston  8 ,  Ronald D Cohn  9 ,  Fernando Scaglia  10 ,  Jill A Rosenfeld  11 ,  Jennifer Tarpinian  12 ,  Cara M Skraban  13 ,  Matthew A Deardorff  13 ,  Jeremy N Friedman  14 ,  Zeynep Coban Akdemir  15 ,  Nicole Walley  1 ,  Mohamad A Mikati  16 ,  Peter G Kranz  17 ,  Joan Jasien  16 ,  Allyn McConkie-Rosell  1 ,  Marie McDonald  1 ,  Stephanie Burns Wechsler  18 ,  Michael Freemark  19 ,  Sujay Kansagra  16 ,  Sharon Freedman  20 ,  Deeksha Bali  21 ,  Francisca Millan  22 ,  Sherri Bale  22 ,  Stanley F Nelson  23 ,  Hane Lee  24 ,  Naghmeh Dorrani  25 ,  UCLA Clinical Genomics Center ,  Undiagnosed Diseases Network ,  David B Goldstein  7 ,  Rui Xiao  2 ,  Yaping Yang  2 ,  Jennifer E Posey  26 ,  Julian A Martinez-Agosto  27 ,  James R Lupski  28 ,  Michael F Wangler  29 ,  Vandana Shashi  30
Affiliations
  • 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: [email protected].
  • 30. Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA. Electronic address: [email protected].
PMID: 28132692 DOI: 10.1016/j.ajhg.2016.12.013
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.