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Exome Sequencing Identifies A Branch Point Variant in Aarskog–Scott Syndrome
Author(s) -
Aten Emmelien,
Sun Yu,
Almomani Rowida,
Santen Gijs W.E.,
Messemaker Tobias,
Maas Saskia M.,
Breuning Martijn H.,
den Dunnen Johan T.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22252
Subject(s) - sanger sequencing , exome sequencing , biology , genetics , exon , exome , point mutation , gene , dna sequencing , mutation , computational biology
Aarskog– S cott syndrome ( ASS ) is a rare disorder with characteristic facial, skeletal, and genital abnormalities. Mutations in the FGD1 gene ( X p11.21) are responsible for ASS . However, mutation detection rates are low. Here, we report a family with ASS where conventional Sanger sequencing failed to detect a pathogenic change in FGD1 . To identify the causative gene, we performed whole‐exome sequencing in two patients. An initial analysis did not reveal a likely candidate gene. After relaxing our filtering criteria, accepting larger intronic segments, we unexpectedly identified a branch point ( BP ) variant in FGD1 . Analysis of patient‐derived RNA showed complete skipping of exon 13, leading to premature translation termination. The BP variant detected is one of very few reported so far proven to affect splicing. Our results show that besides digging deeper to reveal nonobvious variants, isolation and analysis of RNA provides a valuable but under‐appreciated tool to resolve cases with unknown genetic defects.