Biallelic variants in <i>DNA2</i> cause poikiloderma with congenital cataracts and severe growth failure reminiscent of Rothmund-Thomson syndrome

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1
Tipo de produção
article
Data de publicação
2023
DOI
Scopus
Web of Science
PubMed
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Título da Revista
ISSN da Revista
Título do Volume
Editora
BMJ PUBLISHING GROUP
Autores
LAZZARO FILHO, Ricardo Di
SILVA, Tiago J.
ROCHA, Leticia A.
BARTHOLDI, Deborah
SCHALLER, Andre
LEEB, Tosso
Citação
JOURNAL OF MEDICAL GENETICS, v.60, n.11, p.1127-1132, 2023
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Rothmund-Thomson syndrome (RTS) is a rare, heterogeneous autosomal recessive genodermatosis, with poikiloderma as its hallmark. It is classified into two types: type I, with biallelic variants in ANAPC1 and juvenile cataracts, and type II, with biallelic variants in RECQL4, increased cancer risk and no cataracts. We report on six Brazilian probands and two siblings of Swiss/Portuguese ancestry presenting with severe short stature, widespread poikiloderma and congenital ocular anomalies. Genomic and functional analysis revealed compound heterozygosis for a deep intronic splicing variant in trans with loss of function variants in DNA2, with reduction of the protein levels and impaired DNA double-strand break repair. The intronic variant is shared by all patients, as well as the Portuguese father of the European siblings, indicating a probable founder effect. Biallelic variants in DNA2 were previously associated with microcephalic osteodysplastic primordial dwarfism. Although the individuals reported here present a similar growth pattern, the presence of poikiloderma and ocular anomalies is unique. Thus, we have broadened the phenotypical spectrum of DNA2 mutations, incorporating clinical characteristics of RTS. Although a clear genotype-phenotype correlation cannot be definitively established at this moment, we speculate that the residual activity of the splicing variant allele could be responsible for the distinct manifestations of DNA2-related syndromes.
Palavras-chave
Genetics, Medical, DNA Repair, Congenital, Hereditary, and Neonatal Diseases and Abnormalities, Founder Effect
URI
https://observatorio.fm.usp.br/handle/OPI/58951
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MPE