Exome sequencing identifies variants in infants with sacral agenesis

UW Center for Mendelian Genomics, NISC Comparative Sequencing Program and the National Birth Defects Prevention Study

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)215-227
Number of pages13
JournalBirth Defects Research
Volume114
Issue number7
DOIs
StatePublished - Apr 2022

Bibliographical note

Funding Information:
We thank the National Birth Defects Prevention Study participants, scientists, staff, and Genetics Collaborative Working Group. We also thank the Genome Aggregation Database and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/about . This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, the National Institutes of Health, or the California Department of Public Health. This work was funded by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract numbers HHSN275201100001I and HHSN27500005 and by the Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health. This work was also supported through Centers for Disease Control and Prevention cooperative agreements under PA #96043, PA #02081, FOA #DD09‐001, FOA #DD13‐003, and NOFO #DD18‐001 to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention Study and/or the Birth Defects Study To Evaluate Pregnancy exposureS, and the Iowa Center for Birth Defects Research and Prevention U01 DD001035 and U01 DD001223. The University of Washington Center for Mendelian Genomics was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grants UM1 HG006493 and U24 HG008956.

Funding Information:
We thank the National Birth Defects Prevention Study participants, scientists, staff, and Genetics Collaborative Working Group. We also thank the Genome Aggregation Database and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/about. This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, the National Institutes of Health, or the California Department of Public Health. This work was funded by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract numbers HHSN275201100001I and HHSN27500005 and by the Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health. This work was also supported through Centers for Disease Control and Prevention cooperative agreements under PA #96043, PA #02081, FOA #DD09-001, FOA #DD13-003, and NOFO #DD18-001 to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention Study and/or the Birth Defects Study To Evaluate Pregnancy exposureS, and the Iowa Center for Birth Defects Research and Prevention U01 DD001035 and U01 DD001223. The University of Washington Center for Mendelian Genomics was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grants UM1 HG006493 and U24 HG008956. None declared, except that Dr. Finnell was formerly in a leadership position with TeratOmic Consulting LLC, a now dissolved consulting firm.

Publisher Copyright:
© 2022 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Keywords

  • ID1
  • birth defects
  • congenital abnormality
  • sacral agenesis
  • variant

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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