Exome sequencing identifies variants in infants with sacral agenesis

Area of Science:

• Genetics
• Developmental Biology
• Pediatrics

Background:

• Sacral agenesis (SA) is a birth defect involving the spine's caudal end, often with other anomalies.
• Previous research focused on syndromic SA gene variants; limited exome data exists for non-syndromic SA.
• Maternal pregestational diabetes is a known risk factor for SA.

Purpose of the Study:

• To investigate gene variants associated with non-syndromic sacral agenesis (SA).
• To explore potential genetic links beyond maternal diabetes in SA etiology.
• To identify novel candidate genes for non-syndromic SA.

Main Methods:

• Exome sequencing was performed on 28 child-parent trios and 2 child-father duos with non-syndromic SA.
• Buccal cell specimens were used for DNA extraction.
• Variant analysis included assessment of missense, de novo, and inheritance patterns (autosomal recessive, X-linked recessive).

Main Results:

• Heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1) were found in three children, with CADD scores indicating high deleteriousness.
• Two of the three ID1 variants were paternally inherited, and one was maternally inherited.
• Rare missense variants were also identified in PDZD2 and SPTBN5; 12 de novo variants were detected across different genes.

Conclusions:

• This study is the first to suggest a possible association between ID1 variants and non-syndromic SA.
• Paternal inheritance of ID1 variants was observed, contrasting with the established role of maternal diabetes.
• Findings contribute to understanding the genetic basis of non-syndromic SA and warrant further investigation.