Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Medizinische Genetik und Humangenetik, Berlin, Germany.
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Medizinische Genetik und Humangenetik, Berlin, Germany; Max Planck Institute for Molecular Genetics, RG Development & Disease, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany.
Genet Med. 2023 Nov;25(11):100928. doi: 10.1016/j.gim.2023.100928. Epub 2023 Jul 7.
HOXD13 is an important regulator of limb development. Pathogenic variants in HOXD13 cause synpolydactyly type 1 (SPD1). How different types and positions of HOXD13 variants contribute to genotype-phenotype correlations, penetrance, and expressivity of SPD1 remains elusive. Here, we present a novel cohort and a literature review to elucidate HOXD13 phenotype-genotype correlations.
Patients with limb anomalies suggestive of SPD1 were selected for analysis of HOXD13 by Sanger sequencing, repeat length analysis, and next-generation sequencing. Literature was reviewed for HOXD13 heterozygotes. Variants were annotated for phenotypic data. Severity was calculated, and cluster and decision-tree analyses were performed.
We identified 98 affected members of 38 families featuring 11 different (likely) causative variants and 4 variants of uncertain significance. The most frequent (25/38) were alanine repeat expansions. Phenotypes ranged from unaffected heterozygotes to severe osseous synpolydactyly, with intra- and inter-familial heterogeneity and asymmetry. A literature review provided 160 evaluable affected members of 49 families with SPD1. Computer-aided analysis only corroborated a positive correlation between alanine repeat length and phenotype severity.
Our findings support that HOXD13-protein condensation in addition to haploinsufficiency is the molecular pathomechanism of SPD1. Our data may, also, facilitate the interpretation of synpolydactyly radiographs by future automated tools.
HOXD13 是肢体发育的重要调节因子。HOXD13 中的致病性变异导致 1 型综合征性并指（SPD1）。不同类型和位置的 HOXD13 变异如何导致 SPD1 的基因型-表型相关性、外显率和表现度仍不清楚。在这里，我们提出了一个新的队列并进行了文献回顾，以阐明 HOXD13 的表型-基因型相关性。
选择具有 SPD1 暗示性肢体异常的患者进行 Sanger 测序、重复长度分析和下一代测序分析 HOXD13。对 HOXD13 杂合子进行文献回顾。对变异进行表型数据注释。计算严重程度，并进行聚类和决策树分析。
我们确定了 38 个家族的 98 名受影响成员，这些家族具有 11 种不同的（可能的）致病变异和 4 种意义不明的变异。最常见的（25/38）是丙氨酸重复扩增。表型范围从无症状杂合子到严重的骨性并指，存在个体内和个体间的异质性和不对称性。文献回顾提供了 49 个 SPD1 家族的 160 名可评估的受影响成员。计算机辅助分析仅证实了丙氨酸重复长度与表型严重程度之间存在正相关。
我们的研究结果支持 HOXD13 蛋白凝聚除了杂合不足之外，也是 SPD1 的分子发病机制。我们的数据还可以为未来的自动化工具解释并指的 X 光片提供便利。
