Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the 'molar tooth sign'. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole-exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012-12T>A (75.0%), an allele that has not been reported in non-Japanese populations. Therefore c.6012-12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet-Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes.

Background DNA methylation of gene promoters is associated with transcriptional inactivation. Changes in DNA methylation can lead to differences in gene expression levels and thereby influence disease development. We hypothesized that epigenetics underlies the pathogenesis of minimal change nephrotic syndrome (MCNS). Methods Genome-wide DNA methylation changes between relapse and remission in monocytes (n06) and naive T helper cells (Th0s) (n04) isolated from patients with MCNS were investigated using the microarray-based integrated analysis of methylation by isochizomers (MIAMI) method. We confirmed the MIAMI results using bisulfite-pyrosequencing analysis. Expression analysis was performed using quantitative real-time PCR. Results Three gene loci (GATA2, PBX4, and NYX) were significantly less methylated in Th0s during relapse than in remission, compared to none in monocytes. In addition, the distance distribution from the regression line of all probes in MIAMI was significantly different between monocytes and Th0s. The mRNA levels of the three genes in Th0s were not significantly different between relapse and remission. Conclusions Our results demonstrate that the change in DNA methylation patterns from remission to relapse in MCNS occurs predominantly in Th0s rather than in monocytes and suggest that epigenetic regulation in Th0s underlies the pathogenesis of MCNS.

Congenital nephrotic syndrome of the Finnish type (CNF) is a rare autosomal recessive disorder. The incidence of CNF is relatively high in Finland but considerably lower in other countries. We encountered a male newborn with CNF, associated with compound heterozygous mutations in nephrosis 1, congenital, Finnish type (NPHS1). The patient was admitted to hospital as a preterm infant. Physical and laboratory findings fulfilled the diagnostic criteria of nephrotic syndrome, and were compatible with a diagnosis of CNF, but there was no family history of the disease. On genetic analysis of NPHS1 a paternally derived heterozygous frame-shift mutation caused by an 8 bp deletion, resulting in a stop codon in exon 16 (c.2156-2163 delTGCACTGC causing p.L719DfsX4), and a novel, maternally derived nonsense mutation in exon 15 (c.1978G>T causing p.E660X) were identified. Early genetic diagnosis of CNF is important for proper clinical management and appropriate genetic counseling.

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