Abstract：
Gorlin syndrome can be caused by pathogenic/likely pathogenic (P/LP) variants in the tumor suppressor gene PTCH1 (9q22.1-q31), which encodes the receptor for the sonic hedgehog (SHH) ligand. We present a 12-month-old boy clinically diagnosed with Gorlin syndrome who was found to have significantly delayed development, palmar pitting, palmar and plantar keratosis, short hands, frontal bossing, coarse face, hypertelorism, a bifid rib, misaligned and missing teeth, and SHH-activated medulloblastoma. Genetic testing, including a pediatric cancer panel and genome sequencing with peripheral blood, failed to identify any P/LP variants in PTCH1. Paired tumor/normal exome sequencing was performed, which identified a germline NM_000264.5 (PTCH1): c.361_362ins? alteration through manual review of sequencing reads. Clinical RNA sequencing further demonstrated an Alu insertion at this region (PTCH1: c.361_362insAlu), providing molecular confirmation of Gorlin syndrome. This finding exemplifies a unique mechanism for PTCH1 disruption in the germline and highlights the importance of comprehensive analysis, including manual review of DNA sequencing reads and the utility of RNA analysis to detect variant types which may not be identified by routine genetic screening techniques.
摘要：
Gorlin综合征可由肿瘤抑制基因PTCH1（9q22.1-q31）中的致病性/可能致病性（P/LP）变体引起，它编码Sonichedgehog（SHH）配体的受体。我们介绍了一个12个月大的男孩，临床诊断为Gorlin综合征，发现他的发育明显延迟，手掌点蚀,手掌和足底角化病,手短,额前带，粗糙的面,超端粒,两裂肋骨,错位和缺失的牙齿，和SHH激活的髓母细胞瘤.基因检测,包括儿科癌症小组和外周血基因组测序，未能在PTCH1中鉴定任何P/LP变体。配对肿瘤/正常外显子组测序，确定了种系NM_000264.5（PTCH1）：c.361_362ins？通过手动检查测序读数进行改变。临床RNA测序进一步证明了在该区域的Alu插入（PTCH1：c.361_362insAlu），提供Gorlin综合征的分子确认。这一发现体现了种系PTCH1破坏的独特机制，并强调了综合分析的重要性。包括DNA测序读数的手动审查和RNA分析的实用性，以检测可能无法通过常规遗传筛选技术鉴定的变异类型。
