Mutational spectrum of the oral-facial-digital type I syndrome: a study on a large collection of patients

Abstract

Oral-facial-digital type I (OFDI) syndrome is a male-lethal X-linked dominant developmental disorder belonging to the heterogeneous group of oral-facial-digital syndromes (OFDS). OFDI is characterized by malformations of the face, oral cavity, and digits. Central nervous system (CNS) abnormalities and cystic kidney disease can also be part of this condition. This rare genetic disorder is due to mutations in the OFD1 gene that encodes a centrosome/basal body protein necessary for primary cilium assembly and for left-right axis determination, thus ascribing OFDI to the growing number of disorders associated to ciliary dysfunction. We now report a mutation analysis study in a cohort of 100 unrelated affected individuals collected worldwide. Putative disease-causing mutations were identified in 81 patients (81%). We describe 67 different mutations, 64 of which represent novel mutations, including 36 frameshift, nine missense, 11 splice-site, and 11 nonsense mutations. Most of them concentrate in exons 3, 8, 9, 12, 13, and 16, suggesting that these exons may represent mutational hotspots. Phenotypic characterization of the patients provided a better definition of the clinical features of OFDI syndrome. Our results indicate that renal cystic disease is present in 60% of cases >18 years of age. Genotype-phenotype correlation did not reveal significant associations apart for the high-arched/cleft palate most frequently associated to missense and splice-site mutations. Our results contribute to further expand our knowledge on the molecular basis of OFDI syndrome.

Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance

“…The pattern of inheritance is X-linked dominant, being lethal in males, and the related genetic syndrome is characterized by craniofacial and digital abnormalities, as well as polycystic kidneys. 48 Although the function of OFD1 is still not fully elucidated, it is a basal body/centrosome-related protein, localized at the base of primary cilia in fully differentiated cells. 32,33 The cilium is a single microtubule-based structure that emanates from the surface of most cell types in the human body.…”

Expanding the molecular basis and phenotypic spectrum of X-linked Joubert syndrome associated with OFD1 mutations

“…The mutations identified in patients with OFD1 are predominantly truncating, with the few reported missense mutations clustering in a LisH motif in exon 3. 8,12 To our knowledge, mutations in exon 8 have all been splice site or frameshift. Our family with a six amino-acid in-frame deletion in exon 8 demonstrates that the relationship between location and phenotype is more complex than initially hypothesized.…”

Orofacial digital syndrome type 1: an underlying cause of chronic renal failure

“…Diagnosis of chronic renal failure is not common in ADPRD before age of 40 years; however, in Type 1 OFD, diagnosis is usually made based on renal findings after age of 18 years. 5 Oral findings of malposition of teeth, cleft tongue and history of nodule excision on tongue were related with OFD syndrome Type 1. Facial finding was micrognathism, while brachydactyly was found in both fingers and toes.…”