Department of Neurology, Washington University in St Louis, St Louis, MO, USA.
Department of Pediatrics, Washington University in St Louis, St Louis, MO, USA.
Eur J Med Genet. 2022 Jun;65(6):104514. doi: 10.1016/j.ejmg.2022.104514. Epub 2022 Apr 27.
Congenital vertical talus (CVT), also known as "rocker-bottom foot", is a rare foot deformity associated with a dislocation of the talonavicular joint. Although genetic causes of CVT have been described in single isolated and syndromic families, whole-exome sequencing (WES) of large cohorts have not yet been reported.
In this study, 62 probands with CVT were evaluated for likely causative single nucleotide variants (SNVs) and copy number variants (CNVs) using WES. Segregation of variants within families was determined by Sanger sequencing.
In this cohort, CVT occurred as an isolated anomaly in 75.8% (47/62) and was familial in 19.3% (12/62) of cases. Analysis of WES data led to the identification of likely causative variants in known disease genes in 30.6% (19/62) of all CVT probands. More than one proband had likely causative SNVs in TSHZ1, GDF5, and LMX1B. Only two probands had likely causative CNVs: a chromosome 12q13.13 deletion of the 5' HOXC gene cluster, and a chromosome 18q22.3q23 deletion involving TSHZ1. Familial CVT was strongly predictive of identifying a molecular diagnosis [75% (9/12) of familial cases compared to 20% (10/50) of non-familial cases (Chi-square test, P-value = 0.0002)]. There was no difference in the solved rate based on isolated or syndromic presentation, unilateral or bilateral affectation, or sex.
CVT is genetically heterogeneous and more often caused by SNVs than CNVs. There is a high yield of WES in familial CVT cases (∼75%). Additional research is needed to identify the causes of sporadic CVT, which had much lower solved rates.
先天性垂直距骨（CVT），又称“摇椅底足”，是一种罕见的足部畸形，伴有距跟关节脱位。虽然已经在单个孤立的和综合征家族中描述了 CVT 的遗传原因，但尚未报道大规模外显子组测序（WES）的结果。
本研究对 62 例 CVT 患者进行了可能的致病单核苷酸变异（SNV）和拷贝数变异（CNV）的 WES 评估。通过 Sanger 测序确定家系内变异的分离。
在本队列中，75.8%（47/62）的 CVT 为孤立性异常，19.3%（12/62）的病例为家族性。WES 数据分析导致在所有 CVT 先证者中确定了 30.6%（19/62）的已知疾病基因的可能致病变异。超过一个先证者有 TSHZ1、GDF5 和 LMX1B 中的可能致病 SNV。仅有两个先证者有可能致病的 CNV：HOXC 基因簇 5'端的 12q13.13 缺失和涉及 TSHZ1 的 18q22.3q23 缺失。家族性 CVT 强烈提示能识别分子诊断[75%（9/12）的家族性病例与 20%（10/50）的非家族性病例相比（卡方检验，P 值=0.0002)]。基于孤立性或综合征表现、单侧或双侧受累或性别，解决率没有差异。
CVT 是遗传异质性的，由 SNV 引起的情况比 CNV 更常见。在家族性 CVT 病例中，WES 的检出率很高（约 75%）。需要进一步研究以确定散发性 CVT 的病因，其解决率要低得多。
