Exome sequencing identifies variants in infants with sacral agenesis

Georgia Pitsava; Marcia L Feldkamp; Nathan Pankratz; John Lane; Denise M Kay; Kristin M Conway; Gary M Shaw; Jennita Reefhuis; Mary M Jenkins; Lynn M Almli; Cynthia Moore; Martha Werler; Marilyn L Browne; Chris Cunniff; Andrew F Olshan; Faith Pangilinan; Lawrence C Brody; Robert J Sicko; Richard H Finnell; Michael J Bamshad; Daniel McGoldrick; Deborah A Nickerson; James C Mullikin; Paul A Romitti; James L Mills; UW Center for Mendelian Genomics; NISC Comparative Sequencing Program; National Birth Defects Prevention Study

doi:10.1002/bdr2.1987

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Exome sequencing identifies variants in infants with sacral agenesis

Journal article

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Exome sequencing identifies variants in infants with sacral agenesis

Georgia Pitsava, Marcia L Feldkamp, Nathan Pankratz, John Lane, Denise M Kay, Kristin M Conway, Gary M Shaw, Jennita Reefhuis, Mary M Jenkins, Lynn M Almli, …

Birth defects research, Vol.114(7), pp.215-227

03/10/2022

DOI: 10.1002/bdr2.1987

PMCID: PMC9338687

PMID: 35274497

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Abstract

Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non-syndromic SA. Using buccal cell specimens from families of children with non-syndromic SA, exomes of 28 child-parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child-father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced. Three children had heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1), with CADD scores >20 (top 1% of deleterious variants in the genome); two children inherited the variant from their fathers and one from the child's mother. Rare missense variants were also detected in PDZD2 (PDZ Domain Containing 2; N = 1) and SPTBN5 (Spectrin Beta, Non-erythrocytic 5; N = 2), two genes previously suggested to be associated with SA etiology. Examination of variants with autosomal recessive and X-linked recessive inheritance identified five and two missense variants, respectively. Compound heterozygous variants were identified in several genes. In addition, 12 de novo variants were identified, all in different genes in different children. To our knowledge, this is the first study reporting a possible association between ID1 and non-syndromic SA. Although maternal pregestational diabetes has been strongly associated with SA, the missense variants in ID1 identified in two of three children were paternally inherited. These findings add to the knowledge of gene variants associated with non-syndromic SA and provide data for future studies.

sacral agenesis

ID1

variant

congenital abnormality

birth defects

Details

Title: Subtitle: Exome sequencing identifies variants in infants with sacral agenesis
Creators: Georgia Pitsava - Eunice Kennedy Shriver National Institute of Child Health and Human Development
Marcia L Feldkamp - University of Utah
Nathan Pankratz - University of Minnesota Medical School
John Lane - University of Minnesota Medical School
Denise M Kay - Wadsworth Center
Kristin M Conway - University of Iowa
Gary M Shaw - Stanford University School of Medicine
Jennita Reefhuis - National Center on Birth Defects and Developmental Disabilities
Mary M Jenkins - National Center on Birth Defects and Developmental Disabilities
Lynn M Almli - National Center on Birth Defects and Developmental Disabilities
Cynthia Moore - National Center on Birth Defects and Developmental Disabilities
Martha Werler - Boston University
Marilyn L Browne - Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, USA
Chris Cunniff - Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA
Andrew F Olshan - Department of Epidemiology, Gillings School of Global Public Health, Chapel Hill, North Carolina, USA
Faith Pangilinan - National Human Genome Research Institute
Lawrence C Brody - National Human Genome Research Institute
Robert J Sicko - Wadsworth Center
Richard H Finnell - Baylor College of Medicine
Michael J Bamshad - University of Washington
Daniel McGoldrick - University of Washington
Deborah A Nickerson - University of Washington
James C Mullikin - National Human Genome Research Institute
Paul A Romitti - University of Iowa
James L Mills - Eunice Kennedy Shriver National Institute of Child Health and Human Development
UW Center for Mendelian Genomics
NISC Comparative Sequencing Program
National Birth Defects Prevention Study
Resource Type: Journal article
Publication Details: Birth defects research, Vol.114(7), pp.215-227
DOI: 10.1002/bdr2.1987
PMID: 35274497
PMCID: PMC9338687
NLM abbreviation: Birth Defects Res
ISSN: 2472-1727
eISSN: 2472-1727
Publisher: Wiley
Grant note: CDC HHS Eunice Kennedy Shriver National Institute of Child Health and Human Development California Department of Public Health University of Minnesota NHLBI NIH HHS NHGRI NIH HHS NIH HHS
Language: English
Date published: 03/10/2022
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9984227002002771

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