Kim Gabriela Jeesoo, Vasco de Albuquerque Albuquerque Edoarda, Rezende Raissa C, De Polli Cellin Laurana, Santillan Vasconez Ana Maria, Krepischi Ana C V, Santana Lucas, Lerario Antônio Marcondes, de Souza Vinicius, Scalco Renata, Jorge Alexander A L
Endocr Connect. 2025 Jul 15;14(7). doi: 10.1530/EC-25-0137. Print 2025 Jul 1.
This study aimed to evaluate a cohort of patients with syndromic tall stature of unknown etiology via exome sequencing (ES) to identify novel candidate genes for overgrowth conditions. We enrolled 37 patients with heights greater than the 97.7th percentile and syndromic features. The ES analysis first focused on rare deleterious single nucleotide and copy number variants in genes previously associated with overgrowth conditions. For patients in whom diagnosis of a known tall stature disorder could not be achieved, we performed analysis for candidate genes. The search considered deleterious variants in constrained genes that were linked with height in association studies, animal models consistent with the proposed phenotype, and/or variants recurrent in the literature or our cohort. Genetic diagnosis was established in 11 patients. Pathogenic or likely pathogenic variants were identified in FBN1, PTEN, NSD1, SUZ12, CDH8, and DEPDC5. One patient carried a likely pathogenic mutation in FBN2 and a pathogenic mutation in COL5A1. Furthermore, in two patients, we identified large pathogenic deletions confirmed by chromosomal microarray analysis. Candidate gene analysis uncovered four genes potentially associated with tall stature in five patients: PTCH1, SST, KDM4A, and GRB10. PTCH1 and SST were identified in patients with whole gene deletions. Two unrelated patients were found to have the same rare missense variant in KDM4A. In conclusion, exome sequencing analysis had a diagnostic yield of 29.7% in a cohort of patients with syndromic tall stature and we identified four novel candidate genes that are involved in overgrowth conditions.
本研究旨在通过外显子组测序（ES）评估一组病因不明的综合征性身材高大患者，以鉴定与过度生长相关的新候选基因。我们纳入了37例身高高于第97.7百分位数且具有综合征特征的患者。ES分析首先聚焦于先前与过度生长相关的基因中的罕见有害单核苷酸和拷贝数变异。对于无法确诊已知身材高大疾病的患者，我们对候选基因进行了分析。搜索考虑了在关联研究中与身高相关的受限基因中的有害变异、与拟表型一致的动物模型，和/或文献或我们队列中反复出现的变异。11例患者得以确诊。在FBN1、PTEN、NSD1、SUZ12、CDH8和DEPDC5中鉴定出了致病性或可能致病性变异。1例患者在FBN2中携带一个可能致病性突变，在COL5A1中携带一个致病性突变。此外，在2例患者中，我们通过染色体微阵列分析确认了大的致病性缺失。候选基因分析在5例患者中发现了4个可能与身材高大相关的基因：PTCH1、SST、KDM4A和GRB10。PTCH1和SST在全基因缺失的患者中被鉴定出来。发现2例无关患者在KDM4A中具有相同的罕见错义变异。总之，外显子组测序分析在一组综合征性身材高大患者中的诊断率为29.7%，我们鉴定出了4个与过度生长相关的新候选基因。
