title: A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.
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.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Schoch
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
authors.forename: Linyan
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Szelinger
authors.affiliation: Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, Rochester, NY 14627, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Bearden
authors.affiliation: 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.
authors.forename: Asbjorg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway.
authors.forename: Oyvind L
authors.initials: OL
authors.lastname: Busk
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stong
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Eriskay
authors.initials: E
authors.lastname: Liston
authors.affiliation: 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.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Cohn
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Scaglia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tarpinian
authors.affiliation: 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.
authors.forename: Cara M
authors.initials: CM
authors.lastname: Skraban
authors.affiliation: 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.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Friedman
authors.affiliation: Norwegian National Unit for Newborn Screening, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: Zeynep Coban
authors.initials: ZC
authors.lastname: Akdemir
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Walley
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
authors.forename: Mohamad A
authors.initials: MA
authors.lastname: Mikati
authors.affiliation: Division of Neuroradiology, Department of Radiology, Duke Health, Durham, NC 27710, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kranz
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Jasien
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
authors.forename: Allyn
authors.initials: A
authors.lastname: McConkie-Rosell
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: McDonald
authors.affiliation: 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.
authors.forename: Stephanie Burns
authors.initials: SB
authors.lastname: Wechsler
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Freemark
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
authors.forename: Sujay
authors.initials: S
authors.lastname: Kansagra
authors.affiliation: Duke Eye Center, Duke Health, Durham, NC 27710, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Freedman
authors.affiliation: Department of Pathology, Duke Health, Durham, NC 27710, USA.
authors.forename: Deeksha
authors.initials: D
authors.lastname: Bali
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Millan
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Sherri
authors.initials: S
authors.lastname: Bale
authors.affiliation: 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.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: 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.
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Naghmeh
authors.initials: N
authors.lastname: Dorrani
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Posey
authors.affiliation: 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.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Martinez-Agosto
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: 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.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wangler
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA. Electronic address: vandana.shashi@duke.edu.
authors.forename: Vandana
authors.initials: V
authors.lastname: Shashi
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001921:Brain / Q000000981:diagnostic imaging; D002386:Cataract / Q000000981:diagnostic imaging / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000000981:diagnostic imaging / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000235:genetics; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*; D013036:Spasms, Infantile / Q000000981:diagnostic imaging / Q000235:genetics*
chemical_list: C516477:NACC1 protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins
keywords: NACC1; cataracts; developmental/intellectual disabilities; epilepsy; irritability; microcephaly; stereotypy; whole-exome sequencing