ESPE Abstracts (2015) 84 P-2-523

aUnidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil; bDepartamento de Genética e Biologia Evolutiva, Instituto de Biociências da Universidade de São Paulo IBUSP, Sao Paulo, Brazil; cUnidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil

Background: The aetiology of congenital hypopituitarism (CH) is unknown in the majority of patients. In our cohort of 200 cases, it was possible to establish the genetic cause in only 13 patients (6.5%). Copy number variants (CNVs) have been implicated as the cause of genetic syndromes with previously unknown aetiology.

Objective: To study the presence of CNVs and its relevance in patients with CH of unknown cause associated with complex phenotypes.

Patients and methods: 35 patients were selected for whole-genome array-CGH screening in a customised platform of 180 K (Oxford Gene Technologies).

Results: Among the 35 selected patients, ten had septo-optic dysplasia (SOD); six had developmental delay/intellectual disability (DD/ID) and four had midline craniofacial malformations. In this cohort 15 patients (43%) presented CNVs: 13 were considered as variants of uncertain clinical significance (VOUS) and two were considered pathogenic. Among the patients with CNVs, four of them had well-defined genetic syndromes: trichorhinophalangeal syndrome, Rubinstein-Taybi syndrome, Joubert syndrome and PHACE syndrome. Among the CNVs, seven were heterozygous deletions with sizes ranging from 27 Kb to 10.5 Mb, seven were duplications ranging from 55 KB to 1.3 Mb and in one patient two CNVs were found. The pathogenic CNVs were identified in two patients: one patient with the trichorhinophalangeal syndrome, a deletion of 10.5 Mb in chromosome eitht (8q23.1–q24.11) and one patient with Rubinstein-Taybi syndrome with a terminal duplication of 14.7 Mb in chromosome two and a terminal deletion of 4 Mb in chromosome four (two CNVs).

Conclusion: CNVs could explain the genetic aetiology of two patients with syndromic CH. Variants of uncertain clinical significance may also be implicated in the aetiology of CH but further studies are necessary to establish the role of each CNV.

Funding: This work was supported by the National Council for Scientific and Technological Development (CNPq) (grant numbers 305743/2011-2 to B.B.M. and 304678/2012-0 to A.A.L.J.) and Sao Paulo Research Foundation (FAPESP) (grant number 2013/03236-5 to A.A.L.J.).

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