Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Birth Defects Res. 2022 Apr;114(7):215-227. doi: 10.1002/bdr2.1987. Epub 2022 Mar 10.
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.
骶骨发育不全（SA）由脊柱尾部的部分或完全缺失引起，常伴有其他出生缺陷。已有几项研究探讨了综合征型 SA 的基因变异，但仅有一项研究检测了非综合征型 SA 患儿的外显子组。
利用非综合征型 SA 患儿家庭的口腔细胞标本，对 28 个亲子三代（8 个有、20 个无母亲孕前糖尿病诊断）和 2 个父子二代（均无母亲孕前糖尿病诊断）的外显子组进行了测序。
3 名患儿携带 ID1（DNA 结合抑制因子 1）的杂合错义变异，CADD 评分>20（基因组中最有害变异的前 1%）；2 名患儿从父亲、1 名患儿从母亲继承了该变异。还在 PDZD2（PDZ 结构域包含 2 型；N=1）和 SPTBN5（非红细胞 spectrin β5；N=2）中检测到罕见的错义变异，这两个基因先前被认为与 SA 病因有关。对常染色体隐性和 X 连锁隐性遗传的变异进行检查，分别发现了 5 个和 2 个错义变异。在几个基因中鉴定出复合杂合变异。此外，还鉴定出 12 个新生变异，均发生在不同患儿的不同基因中。
据我们所知，这是首次报道 ID1 与非综合征型 SA 之间可能存在关联的研究。虽然孕前糖尿病与 SA 有很强的关联，但在 3 名患儿中的 2 名中发现的 ID1 错义变异是从父亲遗传的。这些发现增加了与非综合征型 SA 相关的基因变异的知识，并为未来的研究提供了数据。
