Department of Human Genetics, Emory University School of Medicine, Atlanta, GA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, Department of Neurology and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Genet Med. 2023 Oct;25(10):100918. doi: 10.1016/j.gim.2023.100918. Epub 2023 Jun 15.
Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls.
We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria.
9.04% of cases and 1.02% of controls had "likely pathogenic" variants (P < .0001), which was almost exclusively driven by heterozygous variants in autosomal genes. Cleft palate (17.6%) and cleft lip and palate (9.09%) cases had the highest yield, whereas cleft lip cases had a 2.80% yield. Out of 39 genes with likely pathogenic variants, 9 genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were "variants of uncertain significance", occurring more frequently in cases (P = .004), but no individual gene showed a significant excess of variants of uncertain significance.
These results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs.
唇腭裂是一种常见的出生缺陷，包括唇裂、唇裂合并腭裂和腭裂。唇腭裂的病因具有异质性，这使得临床诊断变得复杂，因为导致这种疾病的原因并不总是显而易见的，可能是孟德尔遗传、环境或多因素的。目前尚未对孤立性或散发性唇腭裂进行测序；因此，我们对 841 例病例和 294 例对照者的 418 个基因进行了测序分析，以评估其诊断率。
我们使用基因组测序评估了 418 个基因，并对已证实的变异进行了分析，以评估其致病性是否符合美国医学遗传学学院的标准。
9.04%的病例和 1.02%的对照者携带“可能致病性”的变异（P<0.0001），这几乎完全是由常染色体基因的杂合变异驱动的。腭裂（17.6%）和唇裂合并腭裂（9.09%）的病例具有最高的检出率，而唇裂的检出率仅为 2.80%。在具有可能致病性变异的 39 个基因中，包括 CTNND1 和 IRF6 在内的 9 个基因占了一半以上的检出率（占病例的 4.64%）。大多数变异（61.8%）为“意义不明的变异”，在病例中更为常见（P=0.004），但没有任何一个基因的意义不明的变异明显过多。
这些结果强调了唇腭裂的病因异质性，并表明测序可能会缩小唇腭裂的诊断差距。
