title: Genomic deletions of OFD1 account for 23% of oral-facial-digital type 1 syndrome after negative DNA sequencing.
abstract: 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.
authors.affiliation: Centre de Génétique, Hôpital d'Enfants, CHU Dijon, France. christel.thauvin@chu-dijon.fr
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.forename: Brunella
authors.initials: B
authors.lastname: Franco
authors.forename: Pascale
authors.initials: P
authors.lastname: Saugier-Veber
authors.forename: Bernard
authors.initials: B
authors.lastname: Aral
authors.forename: Nadège
authors.initials: N
authors.lastname: Gigot
authors.forename: Anne
authors.initials: A
authors.lastname: Donzel
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: Eric
authors.initials: E
authors.lastname: Bieth
authors.forename: Valérie
authors.initials: V
authors.lastname: Layet
authors.forename: Michèle
authors.initials: M
authors.lastname: Mathieu
authors.forename: Ahmad
authors.initials: A
authors.lastname: Teebi
authors.forename: James
authors.initials: J
authors.lastname: Lespinasse
authors.forename: Patrick
authors.initials: P
authors.lastname: Callier
authors.forename: Francine
authors.initials: F
authors.lastname: Mugneret
authors.forename: Alice
authors.initials: A
authors.lastname: Masurel-Paulet
authors.forename: Elodie
authors.initials: E
authors.lastname: Gautier
authors.forename: Frédéric
authors.initials: F
authors.lastname: Huet
authors.forename: Jean-Raymond
authors.initials: JR
authors.lastname: Teyssier
authors.forename: Mario
authors.initials: M
authors.lastname: Tosi
authors.forename: Thierry
authors.initials: T
authors.lastname: Frébourg
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
mesh_terms: D005260:Female; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D009958:Orofaciodigital Syndromes / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: C115130:OFD1 protein, human; D011506:Proteins