Homozygous loss of function BRCA1 variant causing a Fanconi-anemia-like phenotype, a clinical report and review of previous patients

Autor(es)

Freire, Bruna L. ^{[1, 2, 3]} ; Homma, Thais K. ^{[1, 2, 3]} ; Funari, Mariana F. A. ^[3] ; Lerario, Antonio M. ^[4] ; Leal, Aline M. ^[5] ; Velloso, Elvira D. R. P. ^[5] ; Malaquias, Alexsandra C. ^{[1, 2, 6]} ; Jorge, Alexander A. L. ^{[1, 2, 3]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Unidade Endocrinol Genet LIM25, Hosp Clin HCFMUSP, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Fac Med, Lab Endocrinol Celular & Mol, Hosp Clin HCFMUSP, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Unidade Endocrinol Desenvolvimento, Lab Hormonios & Genet Mol LIM42, Hosp Clin HCFMUSP, Fac Med, Sao Paulo, SP - Brazil

^[4] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA

^[5] Univ Sao Paulo, Hosp Clin HCFMUSP, Lab Citogenet, Unidade Hematol, Fac Med, Sao Paulo, SP - Brazil

^[6] Irmandade Santa Casa Misericordia Sao Paulo, Dept Pediat, Unidade Endocrinol Pediat, Fac Ciencias Med Santa Casa Sao Paulo, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo de Revisão
• Fonte: EUROPEAN JOURNAL OF MEDICAL GENETICS; v. 61, n. 3, p. 130-133, MAR 2018.
• Citações Web of Science: 9

Resumo

Background: Fanconi Anemia (FA) is a rare and heterogeneous genetic syndrome. It is associated with short stature, bone marrow failure, high predisposition to cancer, microcephaly and congenital malformation. Many genes have been associated with FA. Previously, two adult patients with biallelic pathogenic variant in Breast Cancer 1 gene (BRCA1) had been identified in Fanconi Anemia-like condition. Clinical report: The proband was a 2.5 year-old girl with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features. Her parents were third degree cousins. Routine screening tests for short stature was normal. Methods: We conducted whole exome sequencing (WES) of the proband and used an analysis pipeline to identify rare nonsynonymous genetic variants that cause short stature. Results: We identified a homozygous loss-of-function BRCA1 mutation (c.2709T > A; p. Cys903{*}), which promotes the loss of critical domains of the protein. Cytogenetic study with DEB showed an increased chromosomal breakage. We screened heterozygous parents of the index case for cancer and we detected, in her mother, a metastatic adenocarcinoma in an axillar lymph node with probable primary site in the breast. Conclusion: It is possible to consolidate the FA-like phenotype associated with biallelic loss-of-function BRCA1, characterized by microcephaly, short stature, developmental delay, dysmorphic face features and cancer predisposition. In our case, the WES allowed to establish the genetic cause of short stature in the context of a chromosome instability syndrome. An identification of BRCA1 mutations in our patient allowed precise genetic counseling and also triggered cancer screening for the patient and her family members. (AU)

• Processo FAPESP: 13/03236-5 - Novas abordagens e metodologias na investigação genético-molecular dos distúrbios de crescimento e desenvolvimento puberal
• Beneficiário: Alexander Augusto de Lima Jorge
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/26980-7 - Causas genéticas de distúrbio de crescimento de início pré-natal
• Beneficiário: Thais Kataoka Homma
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/02162-8 - Patogênese molecular e caracterização de doenças monogênicas do desenvolvimento: um caminho para a medicina translacional
• Beneficiário: Berenice Bilharinho de Mendonça
• Linha de fomento: Auxílio à Pesquisa - Temático