The analysis in the present series revealed a low frequency of patients presenting with serious clinical findings such as arterial rupture/arterial dissection/aneurysm and perforation or rupture of the gastrointestinal tract, and revealed a higher prevalence of splice-site mutations at the junction of the triple-helical exons than of glycine substitution mutations in COL3A1.

Original research articlePulmonary arterial hypertension (PAH) is a serious disease with a poor prognosis. Possible etiological factors for PAH development include vasospasm, endothelin overactivity, intimal hyperplasia due to increased growth factor secretion, and thrombus formation in small pulmonary arteries.1 The presence of familial disease in ~6% of PAH patients with no obvious secondary causes of PAH suggested that genetic factors play an important role in a substantial proportion of patients with PAH. Linkage analysis and positional cloning have identified mutations in the bone morphogenetic protein type 2 receptor (BMPR2) gene in ~60% of familial PAH (FPAH) cases and 10-40% of patients with idiopathic PAH (IPAH).2-4 BMPR2 mutations were also reported in FPAH patients and in 40% of the IPAH cases in a Japanese population, 5 corresponding to the clinical observation that PAH prevalence does not vary among different races. 6 Recent studies have clarified the presence of genome-wide copy-number variations caused by genomic rearrangement such as deletion, duplication, inversion, and translocation of genetic codes spanning more than 1,000 base pairs, with genetic rearrangements of BMPR2 in patients with FPAH resulting in deletion or duplication of one or more exons of the gene. 7,8 Another study identified exonic deletion or duplication in BMPR2 in both FPAH and IPAH cases.9 These findings have demonstrated that BMPR2 mutations may account for a higher proportion of PAH patients than previously expected.Genome-wide analysis of copy-number variations has indicated significant variation in distribution and frequency among populations with different ethnic backgrounds, although such information about the genetic rearrangements of BMPR2 has been limited to the data obtained. Furthermore, deletion break points in exonic deletions of BMPR2 have not been reported. We therefore undertook a thorough genetic analysis of BMPR2 in Japanese patients with PAH and investigated the deletion break points in exonic deletions of BMPR2. MATERIALS AND METHODS Study populationThe study included PAH patients and their family members in Kyorin University Hospital, Tokyo, Japan, who were enrolled Purpose: The purpose of this study was to undertake thorough genetic analysis of the bone morphogenetic protein type 2 receptor (BMPR2) gene in patients with pulmonary arterial hypertension. Methods:We conducted a systematic analysis for larger gene rearrangements together with conventional mutation analysis in 152 pulmonary arterial hypertension patients including 43 patients diagnosed as having idiopathic pulmonary arterial hypertension and 10 diagnosed as having familial pulmonary arterial hypertension.Results: Analysis of the BMPR2 gene revealed each of the four kinds of nonsense and frameshift mutations, one missense mutation, one splice-site mutation, and two types of exonic deletion. For cases in which exons 1-3 were deleted, the 5′ and 3′ break points were located in the AluY repeat sequences in the 5′ side of the adjacent NOP58 gene...

Recent advances in the analysis of patients with congenital abnormalities using array-based comparative genome hybridization (aCGH) have uncovered two types of genomic copy-number variants (CNVs); pathogenic CNVs (pCNVs) relevant to congenital disorders and benign CNVs observed also in healthy populations, complicating the screening of disease-associated alterations by aCGH. To apply the aCGH technique to the diagnosis as well as investigation of multiple congenital anomalies and mental retardation (MCA/MR), we constructed a consortium with 23 medical institutes and hospitals in Japan, and recruited 536 patients with clinically uncharacterized MCA/MR, whose karyotypes were normal according to conventional cytogenetics, for two-stage screening using two types of bacterial artificial chromosome-based microarray. The first screening using a targeted array detected pCNV in 54 of 536 cases (10.1%), whereas the second screening of the 349 cases negative in the first screening using a genome-wide high-density array at intervals of approximately 0.7 Mb detected pCNVs in 48 cases (13.8%), including pCNVs relevant to recently established microdeletion or microduplication syndromes, CNVs containing pathogenic genes and recurrent CNVs containing the same region among different patients. The results show the efficient application of aCGH in the clinical setting.

We studied the auditory brainstem response (ABR) and neuropathology in a female infant who died at six months of age because of typical infantile Gaucher's disease. The patient was hospitalized for hepatosplenomegaly and failure to thrive. Her ABR showed only waves I and II.The neuropathological study disclosed that: (1) Gaucher's cells were found in the perivascular region of the cerebrum and anterior ventral nucleus of the thalamus. (2) Gliosis was found in the dorsal part of the brainstem rather than the ventral part. (3) Neuronal cells in the superior olivary nucleus were lost, and marked gliosis was found in the cochlear nucleus. The disappearance of wave III and later waves of ABR could be supported by these pathological findings.

SummaryA substantial proportion of patients with pulmonary arterial hypertension (PAH) have mutations in the Bone Morphogenetic Protein Receptor type-2 (BMPR2) gene. PAH due to BMPR2 mutations is inherited as an autosomal dominant trait with several unique features, including a wide variety of mutations, reduced penetrance, a skewed gender ratio, variable expressivity and genetic anticipation. To address the genetic background of these unique features of BMPR2 mutation, we conducted a systematic analysis of 15 PAH families with BMPR2 mutation. The exonic protein coding sequence of BMPR2 was amplified by polymerase chain reaction and the products were sequenced directly to detect point mutations in BMPR2. Parental identification was carried out to confirm the parental relationship using multiplex 15 loci analysis. Combining mutation detection in family members with parental identification, we described three cases of de novo mutation in the BMPR2 gene by different modes in a PAH family. These de novo mutations may account for the wide variety of mutations in BMPR2. Taken together with the juvenile onset of the disease, there is possibly some balance of de novo mutations and untransmittable mutations which keeps the frequency of PAH low in the general population.