McKusick-Zhang Center for Genetic Medicine, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, No.5 Dong Dan San Tiao, Dongcheng District, Beijing, 100005, China.
Laboratory of Clinical Genetics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100073, China.
Orphanet J Rare Dis. 2018 Jul 3;13(1):106. doi: 10.1186/s13023-018-0838-y.
Split hand/foot malformation (SHFM) is a genetically heterogeneous limb malformation with variable expressivity. SHFM with tibia or femur aplasia is called SHFM with long bone deficiency (SHFLD). 17p13.3 duplications containing BHLHA9 are associated with SHFLD. Cases with variable SHFLD phenotype and different 17p13.3 duplicated regions are reported. The severity of long bone defect could not be simply explained by BHLHA9 overdosage or 17p13.3 duplication.
A four-generation Chinese SHFM family was recruited. Three family members have long bone defects, one male was severely affected with hypoplasia or aplasia in three of four limbs. Linkage analysis and direct sequencing of candidate genes were used to exclude six responsible genes/loci for isolated SHFM. Array comparative genomic hybridization (CGH) was performed to detect copy number variations on a genome-wide scale, and quantitative real-time polymerase chain reaction (qPCR) assays were designed to validate the identified copy number variation in the index and other family members.
No mutations were found in genes or loci linked to isolated SHFM. A ~ 966 kb duplication was identified in 17p13.3 by array CGH, in which BHLHA9 surrounding region presented as triplication. The qPCR assays confirmed the indicated 17p13.3 duplication as well as BHLHA9 triplication in all available affected family members and other two asymptomatic carriers. Given the incomplete penetrance in SHFLD, those two carriers were regarded as non-penetrant, which suggested that the genomic rearrangement was co-segregated with malformation in this family.
The present study reports an additional SHFLD family case with 17p13.3 genomic rearrangement. To our knowledge, the 966 kb genomic rearrangement is larger in size than any previously reported SHFLD-associated 17p13.3 duplication, and the present family shows marked phenotypic variability with two asymptomatic carriers and one patient with an extremely severe phenotype. This rare case provides the opportunity to identify underlying genotype-phenotype correlations between SHFLD and 17p13.3 genomic rearrangement.
分裂手/足畸形（SHFM）是一种遗传异质性肢体畸形，具有不同的外显率。伴有胫骨或股骨发育不全的 SHFM 称为伴有长骨发育不全的 SHFM（SHFLD）。17p13.3 内包含 BHLHA9 的重复与 SHFLD 相关。据报道，存在表现型可变的 SHFLD 病例和不同的 17p13.3 重复区域。长骨缺陷的严重程度不能简单地用 BHLHA9 过量或 17p13.3 重复来解释。
招募了一个四代中国 SHFM 家族。三名家族成员存在长骨缺陷，一名男性受影响严重，四肢中有三肢存在发育不全或缺失。使用候选基因的连锁分析和直接测序排除了六个孤立性 SHFM 的致病基因/基因座。进行了全基因组范围的比较基因组杂交（CGH）阵列，以检测拷贝数变异，并设计了定量实时聚合酶链反应（qPCR）检测来验证指数和其他家族成员中确定的拷贝数变异。
未在与孤立性 SHFM 相关的基因或基因座中发现突变。通过 CGH 在 17p13.3 中鉴定出约 966 kb 的重复，其中 BHLHA9 周围区域呈三倍体。qPCR 检测证实了所有可及的受影响家族成员和其他两个无症状携带者中存在的 17p13.3 重复和 BHLHA9 三倍体。鉴于 SHFLD 的不完全外显率，这两个携带者被视为非外显，这表明基因组重排与该家族的畸形共分离。
本研究报告了另一个伴有 17p13.3 基因组重排的 SHFLD 家族病例。据我们所知，该 966 kb 基因组重排的大小大于任何先前报道的与 SHFLD 相关的 17p13.3 重复，本家族表现出明显的表型变异性，有两个无症状携带者和一个患者表现出极为严重的表型。这个罕见的病例为确定 SHFLD 和 17p13.3 基因组重排之间的潜在基因型-表型相关性提供了机会。
