2. Academic Validation
  3. Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders

Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders

  • Am J Hum Genet. 2020 Jan 2;106(1):129-136. doi: 10.1016/j.ajhg.2019.12.006.
Justin O Szot 1,  Carla Campagnolo 2,  Ye Cao 3,  Kavitha R Iyer 1,  Hartmut Cuny 4,  Thomas Drysdale 5,  Josue A Flores-Daboub 6,  Weimin Bi 7,  Lauren Westerfield 8,  Pengfei Liu 7,  Tse Ngong Leung 9,  Kwong Wai Choy 10,  Gavin Chapman 4,  Rui Xiao 7,  Victoria M Siu 11,  Sally L Dunwoodie 12
Affiliations

Affiliations

  • 1 Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, NSW 2010, Australia.
  • 2 Division of Medical Genetics, Department of Pediatrics, University of Western Ontario, London, ON N6A 3K7, Canada.
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR, China; Obstetrics and Gynaecology Centre, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China; Baylor Genetics, Houston, TX 77021, USA.
  • 4 Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
  • 5 Children's Health Research Institute, 800 Commissioners Road East, London, ON N6C 2V5, Canada; Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada; Department of Paediatrics, Western University, 800 Commissioners Road East, London, ON N6A 5W9, Canada.
  • 6 Division of Medical Genetics, Department of Pediatrics, University of Utah, UT 84112, USA.
  • 7 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
  • 8 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 9 Obstetrics and Gynaecology Centre, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China.
  • 10 Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR, China; The Chinese University of Hong Kong-Baylor College of Medicine Joint Center For Medical Genetics, Hong Kong SAR, China.
  • 11 Division of Medical Genetics, Department of Pediatrics, University of Western Ontario, London, ON N6A 3K7, Canada; Children's Health Research Institute, 800 Commissioners Road East, London, ON N6C 2V5, Canada.
  • 12 Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia; Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: s.dunwoodie@victorchang.edu.au.
PMID: 31883644 DOI: 10.1016/j.ajhg.2019.12.006
Abstract

Birth defects occur in up to 3% of all live births and are the leading cause of infant death. Here we present five individuals from four unrelated families, individuals who share similar phenotypes with disease-causal bi-allelic variants in NADSYN1, encoding NAD synthetase 1, the final Enzyme of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway. Defects range from the isolated absence of both kidneys to multiple malformations of the vertebrae, heart, limbs, and kidney, and no affected individual survived for more than three months postnatally. NAD is an essential coenzyme for numerous cellular processes. Bi-allelic loss-of-function mutations in genes required for the de novo synthesis of NAD were previously identified in individuals with multiple congenital abnormalities affecting the heart, kidney, vertebrae, and limbs. Functional assessments of NADSYN1 missense variants, through a combination of yeast complementation and enzymatic assays, show impaired enzymatic activity and severely reduced NAD levels. Thus, NADSYN1 represents an additional gene required for NAD synthesis during embryogenesis, and NADSYN1 has bi-allelic missense variants that cause NAD deficiency-dependent malformations. Our findings expand the genotypic spectrum of congenital NAD deficiency disorders and further implicate mutation of additional genes involved in de novo NAD synthesis as potential causes of complex birth defects.

Keywords

Congenital NAD Deficiency Disorder; NAD; NADSYN1; VACTERL; autosomal recessive; de novo NAD synthesis; kynurenine pathway.

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