No abstract

PLOD2 and FKBP10 are genes mutated in Bruck syndrome (BS), a condition resembling osteogenesis imperfecta (OI), but that is also typically associated with congenital joint contractures. Herein, we sought mutations in six consanguineous BS families and detected changes in either PLOD2 or FKBP10 in all cases. Two probands were found with a homozygous frameshift mutation in the alternative exon 13a of PLOD2, indicating that specific inactivation of the longer protein isoform encoded by this gene is sufficient to cause BS. In addition, by homozygosity mapping, followed by a candidate gene approach, we identified a homozygous donor splice site mutation in PLOD2 in a patient with autosomal-recessive OI (AR-OI). Screening of additional samples also revealed compound heterozygous mutations in PLOD2 in two brothers, one affected with mild AR-OI and the other with mild BS. Thus, PLOD2 in addition to causing BS is also associated with AR-OI phenotypes of variable severity.

Our results suggest that exon 7 skipping in the BSCL2 gene due to the c.985C>T mutation is responsible for a novel early onset, fatal neurodegenerative syndrome involving cerebral cortex and basal ganglia.

Oculoauriculovertebral spectrum (OAVS; OMIM 164210) is characterized by anomalies derived from an abnormal development of the first and second branchial arches, with marked inter and intra-familial phenotypic variability. Main clinical features are defects on aural, oral, mandibular, and vertebral development. Cardiac, pulmonary, renal, skeletal, and central nervous system anomalies have also been described. Most affected individuals are isolated cases in otherwise normal families. Autosomal dominant inheritance has been observed in about 2-10% of cases and linkage analysis as well as array-CGH analysis have detected candidate loci for OAVS offering new insights into the understanding of pathogenesis of this entity. We describe a family with clinical diagnosis of OAVS, autosomal dominant inheritance pattern, and detection of a 14q23.1 duplication of 1.34 Mb in size which segregates with the phenotype. This region contains OTX2, which is involved in the development of the forebrain, eyes, and ears, and appears to be a good candidate gene for OAVS.

The IFITM5 gene has recently been found to be mutated in patients with autosomal dominant osteogenesis imperfecta (OI) type V. This form of OI is characterized by distinctive clinical manifestations, including hyperplastic callus formation at the site of fractures, calcification of the interosseous membrane of the forearm, and dislocation of the head of the radius. Notably, in spite of the fact that a considerable number of patients with IFITM5 mutations have been identified, to date all of them have been shown to have the same heterozygous mutation (c.-14C>T). Herein, we describe one patient with a de novo c.119C>T heterozygous mutation in IFITM5, which predicts p.Ser40Leu, and another with the recurrent c.-14C>T transition that was also apparently de novo. While the patient with the p.Ser40Leu mutation had none of the typical signs of OI type V and was diagnosed with limb shortening at prenatal stages, the patient with the c.-14C>T mutation developed hyperplastic calluses and had calcification of the forearm interosseous membrane. This study challenges the lack of allelic and clinical heterogeneity in IFITM5 mutations.