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Objective: RNF213 was recently reported as a susceptibility gene for moyamoya disease (MMD). Our aim was to clarify the correlation between the RNF213 genotype and MMD phenotype. Methods: The entire coding region of the RNF213 gene was sequenced in 204 patients with MMD, and corresponding variants were checked in 62 pairs of parents, 13 mothers and 4 fathers of the patients, and 283 normal controls. Clinical information was collected. Genotype-phenotype correlations were statistically analyzed. Results: The c.14576G>A variant was identified in 95.1% of patients with familial MMD, 79.2% of patients with sporadic MMD, and 1.8% of controls, thus confirming its association with MMD, with an odds ratio of 259 and p A was observed in 15 patients but not in the controls and unaffected parents. The incidence rate for homozygotes was calculated to be >78%. Homozygotes had a significantly earlier age at onset compared with heterozygotes or wild types (median age at onset 3, 7, and 8 years, respectively). Of homozygotes, 60% were diagnosed with MMD before age 4, and all had infarctions as the first symptom. Infarctions at initial presentation and involvement of posterior cerebral arteries, both known as poor prognostic factors for MMD, were of significantly higher frequency in homozygotes than in heterozygotes and wild types. Variants other than c.14576G>A were not associated with clinical phenotypes. Conclusions: The homozygous c.14576G>A variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy.

Systemic-onset juvenile idiopathic arthritis (s-JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s-JIA remains poorly understood. To detect disease-related copy number variations (CNVs), we performed single-nucleotide polymorphism array analysis in 50 patients with s-JIA. We detected many CNVs, but most of them were inherited from either of normal-phenotype parents. However, in one patient, we could identify two de novo microduplications at 19q13.42 with the size of 77 and 622 kb, separated by a 109-kb segment of normal copy number. The duplications encompass NLRP family (NLRP2, NLRP9 and NLRP11) as well as IL11 and HSPBP1, all of which have an important role in inflammatory pathways. These genes may significantly contribute to the pathogenesis of s-JIA.

Premature ovarian failure (POF) is a disorder characterized by amenorrhea and elevated serum gonadotropins before 40 years of age. As X chromosomal abnormalities are often recognized in POF patients, defects of X-linked gene may contribute to POF. Four cases of POF with t(X;autosome) were genetically analyzed. All the translocation breakpoints were determined at the nucleotide level. Interestingly, COL4A6 at Xq22.3 encoding collagen type IV alpha 6 was disrupted by the translocation in one case, but in the remaining three cases, breakpoints did not involve any X-linked genes. According to the breakpoint sequences, two translocations had microhomology of a few nucleotides and the other two showed insertion of 3-8 nucleotides with unknown origin, suggesting that non-homologous end-joining is related to the formation of all the translocations.

6p duplication syndrome is a rare chromosomal disorder that frequently manifests renal complications, including proteinuria, hypoplastic kidney, and hydronephrosis. We report a girl with the syndrome, manifesting left hydronephrosis, proteinuria/hematuria, and focal segmental glomerular sclerosis (FSGS) resulting in chronic end-stage renal failure, successfully treated with renal transplantation. Microarray comparative genomic hybridization showed the derivative chromosome 6 to have a 6.4-Mb duplication at 6p25.3-p25.1 with 32 protein-coding genes and a 220-Kb deletion at 6p25.3 with two genes of no possible relation to the renal pathology. Review of the literature shows that variation of renal complications in the syndrome is compatible with congenital anomalies of the kidney and urinary tract (CAKUT). FSGS, observed in another patient with 6p duplication syndrome, could be a non-coincidental complication. FOXC1, located within the 6.4-Mb duplicated region at 6p25.3-p25.2, could be a candidate gene for CAKUT, but its single gene duplication effect would not be sufficient. FSGS would be a primary defect associated with duplicated gene(s) albeit no candidate could be proposed, or might occur in association with CAKUT.

RNF213 was recently reported as a susceptibility gene for moyamoya disease (MMD). Our aim was to clarify the correlation between the RNF213 genotype and MMD phenotype.The entire coding region of the RNF213 gene was sequenced in 204 patients with MMD, and corresponding variants were checked in 62 pairs of parents, 13 mothers and 4 fathers of the patients, and 283 normal controls. Clinical information was collected. Genotype-phenotype correlations were statistically analyzed.The c.14576GA variant was identified in 95.1% of patients with familial MMD, 79.2% of patients with sporadic MMD, and 1.8% of controls, thus confirming its association with MMD, with an odds ratio of 259 and p0.001 for either heterozygotes or homozygotes. Homozygous c.14576GA was observed in 15 patients but not in the controls and unaffected parents. The incidence rate for homozygotes was calculated to be78%. Homozygotes had a significantly earlier age at onset compared with heterozygotes or wild types (median age at onset 3, 7, and 8 years, respectively). Of homozygotes, 60% were diagnosed with MMD before age 4, and all had infarctions as the first symptom. Infarctions at initial presentation and involvement of posterior cerebral arteries, both known as poor prognostic factors for MMD, were of significantly higher frequency in homozygotes than in heterozygotes and wild types. Variants other than c.14576GA were not associated with clinical phenotypes.The homozygous c.14576GA variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy.

2q23.1 microdeletion syndrome is a recently characterized chromosomal aberration disorder uncovered through array comparative genomic hybridization (array CGH). Although the cardinal feature is intellectual disability (ID), neurodevelopmental features of the syndrome have not been systematically reviewed. We present a 5-year-old boy with severe psychomotor developmental delay/ID, progressive microcephaly with brain atrophy, growth retardation, and several external anomalies. He manifested intractable epilepsy, effectively treated with combined antiepileptic drug therapy including topiramate. Array CGH demonstrated a de novo interstitial deletion of approximately 1 Mb at 2q23.1–q23.2, involving four genes including MBD5. Nineteen patients have been reported to have the syndrome, including present patient. All patients whose data were available had ID, 17 patients (89%) had seizures, and microcephaly was evident in 9 of 18 patients (50%). Deletion sizes ranged from 200 kb to 5.5 Mb, comprising 1–15 genes. MBD5, the only gene deleted in all patients, is considered to be responsible for ID and epilepsy. Furthermore, the deletion junction was sequenced for the first time in a patient with the syndrome; and homology of three nucleotides, identified at the distal and proximal breakpoints, suggested that the deletion might have been mediated by recently-delineated genomic rearrangement mechanism Fork Stalling and Template Switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR). © 2012 Wiley Periodicals, Inc.

Division of Medical Genetics, Division of Neurology, Gunma Children’s Medical Center, Shibukawa, Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Department of Pediatrics, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan and Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands Correspondence to Yoko Narumi, MD, PhD, Department of Medical Genetics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan Tel: + 81 263 37 2618; fax: + 81 263 37 2619; e-mail: ynarumi@shinshu-u.ac.jp