Laboratorio de Endocrinologia Celular e Molecular LIM25, Unidade de Endocrinologia Genetica/Faculdade de Medicina da Universidade de Sao Paulo (FMUSP)/Hospital das Clinicas da Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
J Pediatr. 2024 Feb;265:113841. doi: 10.1016/j.jpeds.2023.113841. Epub 2023 Nov 22.
To evaluate the presence of multiple genetic diagnoses in syndromic growth disorders.
We carried out a cross-sectional study to evaluate 115 patients with syndromic tall (n = 24) or short stature (n = 91) of unknown cause from a tertiary referral center for growth disorders. Exome sequencing was performed to assess germline single nucleotide, InDel, and copy number variants. All variants were classified according to ACMG/AMP guidelines. The main outcome measured was the frequency of multiple genetic diagnoses in a cohort of children with syndromic growth disorders.
The total diagnostic yield of the cohort was 54.8% (63/115). Six patients had multiple genetic diagnoses (tall stature group = 2; short stature group = 4). The proportion of multiple diagnoses within total cases was 5.2% (6/115), and within solved cases was 9.5% (6/63). No characteristics were significantly more frequent when compared with patients with single or multiple genetic findings. Among patients with multiple diagnoses, 3 had syndromes with overlapping clinical features, and the others had syndromes with distinct phenotypes.
Recognition of multiple genetic diagnoses as a possibility in complex cases of syndromic growth disorders opens a new perspective on treatment and genetic counseling for affected patients, defying the medical common sense of trying to fit all findings into one diagnosis.
评估综合征性生长障碍中存在多种遗传诊断的情况。
我们进行了一项横断面研究，评估了来自一家三级生长障碍转诊中心的 115 名不明原因的综合征性身材高大（n=24）或矮小（n=91）患者。对外显子组进行测序，以评估种系单核苷酸、InDel 和拷贝数变异。所有变异均根据 ACMG/AMP 指南进行分类。主要测量的结果是在一组综合征性生长障碍儿童中多种遗传诊断的频率。
队列的总诊断率为 54.8%（63/115）。6 名患者有多种遗传诊断（身材高大组=2；身材矮小组=4）。在总病例中，多种诊断的比例为 5.2%（6/115），在已解决病例中为 9.5%（6/63）。与单基因或多基因发现的患者相比，没有任何特征明显更频繁。在有多种诊断的患者中，3 人患有具有重叠临床特征的综合征，其他人患有具有不同表型的综合征。
在综合征性生长障碍的复杂病例中，认识到多种遗传诊断的可能性为受影响患者的治疗和遗传咨询开辟了新的视角，这与将所有发现纳入一个诊断的医学共识相悖。
