Exome sequencing identifies variants in infants with sacral agenesis

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.

Maternal Risk Factors for Congenital Vertebral Anomalies

“…Syndromes and minor anomalies were excluded according to the European network of population-based registries for the epidemiological surveillance of congenital anomalies (European Surveillance of Congenital Anomalies [EUROCAT]) 23 , based on the recorded diagnoses at the FRM. Lumbosacral agenesis or caudal regression syndrome represents a separate entity that likely has a different etiology from other vertebral anomalies 24 , and these cases were therefore excluded. Cases with VACTERL or VATER (vertebral defects, anorectal malformation, tracheo-esophageal fistula, renal anomalies) association (which are defined by the presence of at least 3 of the following malformations: vertebral defects, anorectal malformation, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities 25 ) were included in the analysis.…”

Caudal Regression Syndrome—A Narrative Review: An Orthopedic Point of View

“…The recent study reported a possible association between ID1 (inhibitor of DNA Binding 1) and non-syndromic sacral agenesis: the missense variants in ID1 were identified in two of three children (paternally inherited) [ 38 ]. Future studies are, however, necessary.…”