Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brasil.
Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM25, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brasil.
Clin Endocrinol (Oxf). 2018 Mar;88(3):425-431. doi: 10.1111/cen.13535. Epub 2018 Jan 10.
The aetiology of congenital hypopituitarism (CH) is unknown in most patients. Rare copy number variants (CNVs) have been implicated as the cause of genetic syndromes with previously unknown aetiology. Our aim was to study the presence of CNVs and their pathogenicity in patients with idiopathic CH associated with complex phenotypes.
We selected 39 patients with syndromic CH for array-based comparative genomic hybridization (aCGH). Patients with pathogenic CNVs were also evaluated by whole exome sequencing.
Twenty rare CNVs were detected in 19 patients. Among the identified rare CNVs, six were classified as benign, eleven as variants of uncertain clinical significance (VUS) and four as pathogenic. The three patients with pathogenic CNVs had combined pituitary hormone deficiencies, and the associated complex phenotypes were intellectual disabilities: trichorhinophalangeal type I syndrome (TRPS1) and developmental delay/intellectual disability with cardiac malformation, respectively. Patient one has a de novo 1.6-Mb deletion located at chromosome 3q13.31q13.32, which overlaps with the region of the 3q13.31 deletion syndrome. Patient two has a 10.5-Mb de novo deletion at 8q23.1q24.11, encompassing the TRPS1 gene; his phenotype is compatible with TRPS1. Patient three carries a chromosome translocation t(2p24.3;4q35.1) resulting in two terminal alterations: a 2p25.3p24.3 duplication of 14.7 Mb and a 4-Mb deletion at 4q35.1q35.2.
Copy number variants explained the phenotype in 8% of patients with hypopituitarism and additional complex phenotypes. This suggests that chromosomal alterations are an important contributor to syndromic hypopituitarism.
大多数先天性垂体功能减退症（CH）患者的病因未知。罕见的拷贝数变异（CNV）被认为是先前病因不明的遗传综合征的原因。我们的目的是研究与复杂表型相关的特发性 CH 患者中 CNV 的存在及其致病性。
我们选择了 39 名患有综合征性 CH 的患者进行基于阵列的比较基因组杂交（aCGH）。还通过全外显子组测序评估了具有致病性 CNV 的患者。
在 19 名患者中检测到 20 个罕见的 CNV。在所鉴定的罕见 CNV 中，6 个被归类为良性，11 个为意义不明的变异（VUS），4 个为致病性。有 3 名患有致病性 CNV 的患者患有垂体激素联合缺乏症，相关的复杂表型为智力障碍：分别为 trichorhinophalangeal 型 I 综合征（TRPS1）和伴有心脏畸形的发育迟缓/智力障碍。患者 1 具有位于染色体 3q13.31q13.32 上的 1.6-Mb 从头缺失，该缺失与 3q13.31 缺失综合征的区域重叠。患者 2 具有 10.5-Mb 的 8q23.1q24.11 从头缺失，包含 TRPS1 基因；他的表型与 TRPS1 相符。患者 3 携带染色体易位 t(2p24.3;4q35.1)，导致两个末端改变：2p25.3p24.3 处的 14.7 Mb 重复和 4q35.1q35.2 处的 4 Mb 缺失。
CNV 解释了 8%的垂体功能减退症和其他复杂表型患者的表型。这表明染色体改变是综合征性垂体功能减退症的重要原因。
