Exome sequencing identifies variants in infants with sacral agenesis

Georgia Pitsava¹, Marcia L Feldkamp², Nathan Pankratz³, John Lane³, Denise M Kay⁴, Kristin M Conway⁵, Charlotte Hobbs⁶, Gary M Shaw⁷, Jennita Reefhuis⁸, Mary M Jenkins⁸, Lynn M Almli⁸, Cynthia Moore⁸, Martha Werler^{9

10}, Marilyn L Browne^{11

12}, Chris Cunniff¹³, Andrew F Olshan¹⁴, Faith Pangilinan¹⁵, Lawrence C Brody¹⁵, Robert J Sicko⁴, Richard H Finnell¹⁶, Michael J Bamshad¹⁷, Daniel McGoldrick¹⁸, Deborah A Nickerson¹⁸, James C Mullikin¹⁹, Paul A Romitti⁵, James L Mills¹; UW Center for Mendelian Genomics, NISC Comparative Sequencing Program and the National Birth Defects Prevention Study

Collaborators, Affiliations

Collaborators

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

Affiliations

¹ Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
² Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
³ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
⁴ Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
⁵ Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, USA.
⁶ Rady Children's Institute for Genomic Medicine, California, USA.
⁷ Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
⁸ National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
⁹ Slone Epidemiology Center at Boston University, Boston, Massachusetts, USA.
¹⁰ Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.
¹¹ New York State Department of Health, Birth Defects Registry, Albany, New York, USA.
¹² Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, USA.
¹³ Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA.
¹⁴ Department of Epidemiology, Gillings School of Global Public Health, Chapel Hill, North Carolina, USA.
¹⁵ Gene and Environment Interaction Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
¹⁶ Center for Precision Environmental Health, Baylor College of Medicine, Houston, Texas, USA.
¹⁷ Department of Pediatrics, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
¹⁹ National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

PMID: 35274497
PMCID: PMC9338687
DOI: 10.1002/bdr2.1987

Exome sequencing identifies variants in infants with sacral agenesis

Georgia Pitsava et al. Birth Defects Res. 2022 Apr.

. 2022 Apr;114(7):215-227.

doi: 10.1002/bdr2.1987. Epub 2022 Mar 10.

Authors

Collaborators

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

Affiliations

¹ Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
² Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
³ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
⁴ Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
⁵ Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, USA.
⁶ Rady Children's Institute for Genomic Medicine, California, USA.
⁷ Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
⁸ National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
⁹ Slone Epidemiology Center at Boston University, Boston, Massachusetts, USA.
¹⁰ Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.
¹¹ New York State Department of Health, Birth Defects Registry, Albany, New York, USA.
¹² Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, USA.
¹³ Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA.
¹⁴ Department of Epidemiology, Gillings School of Global Public Health, Chapel Hill, North Carolina, USA.
¹⁵ Gene and Environment Interaction Section, National Human Genome Research Institute, Bethesda, Maryland, USA.
¹⁶ Center for Precision Environmental Health, Baylor College of Medicine, Houston, Texas, USA.
¹⁷ Department of Pediatrics, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
¹⁹ National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

PMID: 35274497
PMCID: PMC9338687
DOI: 10.1002/bdr2.1987

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.

Keywords: ID1; birth defects; congenital abnormality; sacral agenesis; variant.

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Conflict of interest statement

Conflicts of interest None declared, except that Dr. Finnell was formerly in a leadership position with TeratOmic Consulting LLC, a now dissolved consulting firm.

References

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1. Aslan H, Yanik H, Celikaslan N, Yildirim G, & Ceylan Y. (2001). Prenatal diagnosis of Caudal Regression Syndrome : a case report. BMC Pregnancy Childbirth, 1(1), 8. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11782287 - PMC - PubMed
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Exome sequencing identifies variants in infants with sacral agenesis

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Exome sequencing identifies variants in infants with sacral agenesis

Authors

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Abstract

Conflict of interest statement

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