Case Reports

. 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

Kelly Schoch¹, Linyan Meng², Szabolcs Szelinger³, David R Bearden⁴, Asbjorg Stray-Pedersen⁵, Oyvind L Busk⁶, Nicholas Stong⁷, Eriskay Liston⁸, Ronald D Cohn⁹, Fernando Scaglia¹⁰, Jill A Rosenfeld¹¹, Jennifer Tarpinian¹², Cara M Skraban¹³, Matthew A Deardorff¹³, Jeremy N Friedman¹⁴, Zeynep Coban Akdemir¹⁵, Nicole Walley¹, Mohamad A Mikati¹⁶, Peter G Kranz¹⁷, Joan Jasien¹⁶, Allyn McConkie-Rosell¹, Marie McDonald¹, Stephanie Burns Wechsler¹⁸, Michael Freemark¹⁹, Sujay Kansagra¹⁶, Sharon Freedman²⁰, Deeksha Bali²¹, Francisca Millan²², Sherri Bale²², Stanley F Nelson²³, Hane Lee²⁴, Naghmeh Dorrani²⁵; UCLA Clinical Genomics Center; Undiagnosed Diseases Network; David B Goldstein⁷, Rui Xiao², Yaping Yang², Jennifer E Posey²⁶, Julian A Martinez-Agosto²⁷, James R Lupski²⁸, Michael F Wangler²⁹, Vandana Shashi³⁰

Collaborators, Affiliations

Collaborators

Stanley F Nelson, Wayne W Grody, Hane Lee, Samuel P Strom, Eric Vilain, Joshua Deignan, Fabiola Quintero-Rivera, Sibel Kantarci, Naghmeh Dorrani, Sureni Mullegama, Sung-Hae Kang, Szabolcs Szelinger, Mercedes E Alejandro, Carlos A Bacino, Ashok Balasubramanyam, Lindsay C Burrage, Gary D Clark, William J Craigen, Shweta U Dhar, Lisa T Emrick, Brett H Graham, Neil A Hanchard, Mahim Jain, Seema R Lalani, Brendan H Lee, Richard A Lewis, Azamian S Mashid, Paolo M Moretti, Sarah K Nicholas, Jordan S Orange, Jennifer E Posey, Lorraine Potocki, Jill A Rosenfeld, Daryl A Scott, Alyssa A Tran, Hugo J Bellen, Michael F Wangler, Shinya Yamamoto, Christine M Eng, Donna M Muzny, Patricia A Ward, Yaping Yang, Andrea L Gropman, David B Goldstein, Nicholas Stong, Yong-Hui Jiang, Allyn McConkie-Rosell, Loren D M Pena, Kelly Schoch, Vandana Shashi, Rebecca C Spillmann, Jennifer A Sullivan, Nicole M Walley, Alan H Beggs, Lauren C Briere, Cynthia M Cooper, Laurel A Donnell-Fink, Elizabeth L Krieg, Joel B Krier, Sharyn A Lincoln, Joseph Loscalzo, Richard L Maas, Calum A MacRae, J Carl Pallais, Lance H Rodan, Edwin K Silverman, Joan M Stoler, David A Sweetser, Chris A Walsh, Cecilia Esteves, Ingrid A Holm, Isaac S Kohane, Paul Mazur, Alexa T McCray, Matthew Might, Rachel B Ramoni, Kimberly Splinter, David P Bick, Camille L Birch, Braden E Boone, Donna M Brown, Dan C Dorset, Lori H Handley, Howard J Jacob, Angela L Jones, Jozef Lazar, Shawn E Levy, J Scott Newberry, Molly C Schroeder, Kimberly A Strong, Elizabeth A Worthey, Jyoti G Dayal, David J Eckstein, Sarah E Gould, Ellen M Howerton, Donna M Krasnewich, Carson R Loomis, Laura A Mamounas, Teri A Manolio, John J Mulvihill, Anastasia L Wise, Ariane G Soldatos, Matthew Brush, Jean-Philippe F Gourdine, Melissa Haendel, David M Koeller, Jennifer E Kyle, Thomas O Metz, Katrina M Waters, Bobbie-Jo M Webb-Robertson, Euan A Ashley, Jonathan A Bernstein, Annika M Dries, Paul G Fisher, Jennefer N Kohler, Daryl M Waggott, Matt T Wheeler, Patricia A Zornio, Patrick Allard, Hayk Barseghyan, Esteban C Dell'Angelica, Katrina M Dipple, Naghmeh Dorrani, Matthew R Herzog, Hane Lee, Stan F Nelson, Christina G S Palmer, Jeanette C Papp, Janet S Sinsheimer, Eric Vilain, Christopher J Adams, Elizabeth A Burke, Katherine R Chao, Mariska Davids, David D Draper, Tyra Estwick, Trevor S Frisby, Kate Frost, Valerie Gartner, Rena A Godfrey, Mitchell Goheen, Gretchen A Golas, Mary Gracie G Gordon, Catherine A Groden, Mary E Hackbarth, Isabel Hardee, Jean M Johnston, Alanna E Koehler, Lea Latham, Yvonne L Latour, C Christopher Lau, Denise J Levy, Adam P Liebendorder, Ellen F Macnamara, Valerie V Maduro, Thomas C Markello, Alexandra J McCarty, Jennifer L Murphy, Michele E Nehrebecky, Donna Novacic, Barbara N Pusey, Sarah Sadozai, Katherine E Schaffer, Prashant Sharma, Sara P Thomas, Nathanial J Tolman, Camilo Toro, Zaheer M Valivullah, Colleen E Wahl, Mike Warburton, Alec A Weech, Guoyun Yu, David R Adams, William A Gahl, May Christine V Malicdan, Cynthia J Tifft, Lynne A Wolfe, Paul R Lee, John H Postlethwait, Monte Westerfield, Anna Bican, Rizwan Hamid, John H Newman, John A Phillips 3rd, Amy K Robertson, Joy D Cogan

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: michael.wangler@bcm.edu.
³⁰ Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA. Electronic address: vandana.shashi@duke.edu.

PMID: 28132692
PMCID: PMC5294886
DOI: 10.1016/j.ajhg.2016.12.013

Case Reports

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

Kelly Schoch et al. Am J Hum Genet. 2017.

. 2017 Feb 2;100(2):343-351.

doi: 10.1016/j.ajhg.2016.12.013. Epub 2017 Jan 26.

Authors

Collaborators

Stanley F Nelson, Wayne W Grody, Hane Lee, Samuel P Strom, Eric Vilain, Joshua Deignan, Fabiola Quintero-Rivera, Sibel Kantarci, Naghmeh Dorrani, Sureni Mullegama, Sung-Hae Kang, Szabolcs Szelinger, Mercedes E Alejandro, Carlos A Bacino, Ashok Balasubramanyam, Lindsay C Burrage, Gary D Clark, William J Craigen, Shweta U Dhar, Lisa T Emrick, Brett H Graham, Neil A Hanchard, Mahim Jain, Seema R Lalani, Brendan H Lee, Richard A Lewis, Azamian S Mashid, Paolo M Moretti, Sarah K Nicholas, Jordan S Orange, Jennifer E Posey, Lorraine Potocki, Jill A Rosenfeld, Daryl A Scott, Alyssa A Tran, Hugo J Bellen, Michael F Wangler, Shinya Yamamoto, Christine M Eng, Donna M Muzny, Patricia A Ward, Yaping Yang, Andrea L Gropman, David B Goldstein, Nicholas Stong, Yong-Hui Jiang, Allyn McConkie-Rosell, Loren D M Pena, Kelly Schoch, Vandana Shashi, Rebecca C Spillmann, Jennifer A Sullivan, Nicole M Walley, Alan H Beggs, Lauren C Briere, Cynthia M Cooper, Laurel A Donnell-Fink, Elizabeth L Krieg, Joel B Krier, Sharyn A Lincoln, Joseph Loscalzo, Richard L Maas, Calum A MacRae, J Carl Pallais, Lance H Rodan, Edwin K Silverman, Joan M Stoler, David A Sweetser, Chris A Walsh, Cecilia Esteves, Ingrid A Holm, Isaac S Kohane, Paul Mazur, Alexa T McCray, Matthew Might, Rachel B Ramoni, Kimberly Splinter, David P Bick, Camille L Birch, Braden E Boone, Donna M Brown, Dan C Dorset, Lori H Handley, Howard J Jacob, Angela L Jones, Jozef Lazar, Shawn E Levy, J Scott Newberry, Molly C Schroeder, Kimberly A Strong, Elizabeth A Worthey, Jyoti G Dayal, David J Eckstein, Sarah E Gould, Ellen M Howerton, Donna M Krasnewich, Carson R Loomis, Laura A Mamounas, Teri A Manolio, John J Mulvihill, Anastasia L Wise, Ariane G Soldatos, Matthew Brush, Jean-Philippe F Gourdine, Melissa Haendel, David M Koeller, Jennifer E Kyle, Thomas O Metz, Katrina M Waters, Bobbie-Jo M Webb-Robertson, Euan A Ashley, Jonathan A Bernstein, Annika M Dries, Paul G Fisher, Jennefer N Kohler, Daryl M Waggott, Matt T Wheeler, Patricia A Zornio, Patrick Allard, Hayk Barseghyan, Esteban C Dell'Angelica, Katrina M Dipple, Naghmeh Dorrani, Matthew R Herzog, Hane Lee, Stan F Nelson, Christina G S Palmer, Jeanette C Papp, Janet S Sinsheimer, Eric Vilain, Christopher J Adams, Elizabeth A Burke, Katherine R Chao, Mariska Davids, David D Draper, Tyra Estwick, Trevor S Frisby, Kate Frost, Valerie Gartner, Rena A Godfrey, Mitchell Goheen, Gretchen A Golas, Mary Gracie G Gordon, Catherine A Groden, Mary E Hackbarth, Isabel Hardee, Jean M Johnston, Alanna E Koehler, Lea Latham, Yvonne L Latour, C Christopher Lau, Denise J Levy, Adam P Liebendorder, Ellen F Macnamara, Valerie V Maduro, Thomas C Markello, Alexandra J McCarty, Jennifer L Murphy, Michele E Nehrebecky, Donna Novacic, Barbara N Pusey, Sarah Sadozai, Katherine E Schaffer, Prashant Sharma, Sara P Thomas, Nathanial J Tolman, Camilo Toro, Zaheer M Valivullah, Colleen E Wahl, Mike Warburton, Alec A Weech, Guoyun Yu, David R Adams, William A Gahl, May Christine V Malicdan, Cynthia J Tifft, Lynne A Wolfe, Paul R Lee, John H Postlethwait, Monte Westerfield, Anna Bican, Rizwan Hamid, John H Newman, John A Phillips 3rd, Amy K Robertson, Joy D Cogan

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: michael.wangler@bcm.edu.
³⁰ Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA. Electronic address: vandana.shashi@duke.edu.

PMID: 28132692
PMCID: PMC5294886
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.

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Figures

**Figure 1**
Clinical and Neuroradiologic Characteristics of the Seven Probands (A) Individual 1 at 20 months of age. (B) Individual 2 at 12 years of age. (C) Individual 3 at 9 years of age. (D) Individual 4 at 3.5 years of age. (E) Individual 6 at 13 months of age. (F) Individual 7 at 12 years of age. (G–P) Axial T1 and T2 brain MRI images demonstrating mildly delayed myelination in individual 1 at 9 months old (G, L); severely delayed myelination and volume loss in individual 4 at 3 years old (H, M); severely delayed myelination and minimal volume loss in individual 5 at 10 years old (I, N); volume loss with normal myelination in individual 6 at 12 months old (J, O); and normal myelination and brain volume in individual 7 at 10 years old (K, P).

**Figure 2**
Recurrent De Novo c.892C>T (p.Arg298Trp) Missense Change in *NACC1* Observed in All Seven Probands (A) Family pedigrees for individuals 1–7 with de novo events in each affected proband. Note that unaffected sibling of individual 5 was also sequenced and found not to have the de novo variant. (B) Sanger sequencing traces for individuals 1–7 showing the heterozygous de novo C-T transition at the c.892 CGG codon encoding arginine, resulting in a TGG codon encoding tryptophan. Individual 7 was found to be mosaic for this variant in peripheral blood. Numbers below each individual represent allele count of alternative to reference alleles from exome sequencing.

**Figure 3**
Predicted Protein Change for the De Novo *NACC1* Variant in Context of Protein Domains (A) Amino acid sequence alignment of human NAC1 with zebrafish, *Xenopus*, and mouse. The BEN and BTB domains are shown, and the location of the p.Arg298Trp missense change is depicted by a red star. The amino acid residue is conserved in all four species and is within a stretch of identical residues. (B) The Arg298 residue occurs within NAC1 between the BTB domain and BEN domain, closer to the BEN domain. A single p.Arg468Cys change (gray-green lollipop) has been noted in a large cohort study of intellectual disability, while the c.946+2T>C (A316 splice) change (black lollipop with asterisk to indicate the position of the splice change) has been noted in a cohort of patients with autism spectrum disorder. Interestingly, a variant involving the same amino acid, converting from Arg to Leu (c.893G>T [p.Arg298Leu]), has been observed once in the ExAC database and in four individuals in gnomAD, with undefined clinical information. Spanning this region is a microdeletion, shown as a gray bar under the gene domain structure.

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References

1. Gonzaga-Jauregui C., Lupski J.R., Gibbs R.A. Human genome sequencing in health and disease. Annu. Rev. Med. 2012;63:35–61. - PMC - PubMed
1. Iossifov I., O’Roak B.J., Sanders S.J., Ronemus M., Krumm N., Levy D., Stessman H.A., Witherspoon K.T., Vives L., Patterson K.E. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515:216–221. - PMC - PubMed
1. Iossifov I., Ronemus M., Levy D., Wang Z., Hakker I., Rosenbaum J., Yamrom B., Lee Y.H., Narzisi G., Leotta A. De novo gene disruptions in children on the autistic spectrum. Neuron. 2012;74:285–299. - PMC - PubMed
1. de Ligt J., Veltman J.A., Vissers L.E. Point mutations as a source of de novo genetic disease. Curr. Opin. Genet. Dev. 2013;23:257–263. - PubMed
1. de Ligt J., Willemsen M.H., van Bon B.W., Kleefstra T., Yntema H.G., Kroes T., Vulto-van Silfhout A.T., Koolen D.A., de Vries P., Gilissen C. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 2012;367:1921–1929. - PubMed

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

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

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