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Genomic deletions of OFD1 account for 23% of oral‐facial‐digital type 1 syndrome after negative DNA sequencing
Author(s) -
ThauvinRobinet Christel,
Franco Brunella,
SaugierVeber Pascale,
Aral Bernard,
Gigot Nadège,
Donzel Anne,
Van Maldergem Lionel,
Bieth Eric,
Layet Valérie,
Mathieu Michèle,
Teebi Ahmad,
Lespinasse James,
Callier Patrick,
Mugneret Francine,
MasurelPaulet Alice,
Gautier Elodie,
Huet Frédéric,
Teyssier JeanRaymond,
Tosi Mario,
Frébourg Thierry,
Faivre Laurence
Publication year - 2009
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.20888
Subject(s) - biology , genetics , dna sequencing , computational biology , dna
Oral‐facial‐digital type I syndrome (OFDI) is characterised by an X‐linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, dental and distal abnormalities, polycystic kidney disease and central nervous system malformations. Considerable allelic heterogeneity has been reported within the OFD1 gene, but DNA bi‐directional sequencing of the exons and intron‐exon boundaries of the OFD1 gene remains negative in more than 20% of cases. We hypothesized that genomic rearrangements could account for the majority of the remaining undiagnosed cases. Thus, we took advantage of two independent available series of patients with OFDI syndrome and negative DNA bi‐directional sequencing of the exons and intron‐exon boundaries of the OFD1 gene from two different European labs: 13/36 cases from the French lab; 13/95 from the Italian lab. All patients were screened by a semiquantitative fluorescent multiplex method (QFMPSF) and relative quantification by real‐time PCR (qPCR). Six OFD1 genomic deletions (exon 5, exons 1–8, exons 1–14, exons 10–11, exons 13–23 and exon 17) were identified, accounting for 5% of OFDI patients and for 23% of patients with negative mutation screening by DNA sequencing. The association of DNA direct sequencing, QFMPSF and qPCR detects OFD1 alteration in up to 85% of patients with a phenotype suggestive of OFDI syndrome. Given the average percentage of large genomic rearrangements (5%), we suggest that dosage methods should be performed in addition to DNA direct sequencing analysis to exclude the involvement of the OFD1 transcript when there are genetic counselling issues. © 2008 Wiley‐Liss, Inc.