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Molecular confirmation of HRAS p.G12S in siblings with Costello syndrome
Author(s) -
Gripp Karen W.,
Stabley Deborah L.,
Geller Peter L.,
Hopkins Elizabeth,
Stevenson David A.,
Carey John C.,
SolChurch Katia
Publication year - 2011
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.34150
Subject(s) - hras , costello syndrome , germline mosaicism , genetics , germline mutation , mutation , biology , monozygotic twin , sibling , macrocephaly , gene , kras , psychology , developmental psychology
Abstract Costello syndrome was first reported based on its characteristic phenotype. Its presentation affects multiple organ systems, including severe failure‐to‐thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto‐oncogene HRAS have been recognized to cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant. Here, we report on the identification of an HRAS mutation c.34G>A, predicting a p.G12S amino acid substitution, in the surviving brother of a previously reported sibling pair, and documentation of the same change in autopsy material from his deceased sister. This represents, to our knowledge, the first molecularly confirmed Costello syndrome in siblings. We did not detect the mutation in a heterozygous state or mosaicism in peripheral white blood cell or cheek swab‐derived DNA samples from either parent. Using single nucleotide polymorphic markers and allele‐specific amplification, we clearly identified the mutation in the surviving sibling to be of maternal origin. While we cannot exclude two independently occurring de novo mutations, the complete sharing of polymorphic markers around the mutation site in both siblings supports maternal germ cell mosaicism. Recurrence risk counseling for families with apparently de novo occurring autosomal dominant conditions includes discussion of germ cell mosaicism, and this report underscores the applicability of this concern to Costello syndrome. © 2011 Wiley‐Liss, Inc.