Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency.

The human Polyomavirus BK (BKV) contains a hypervariable non-coding control region (NCCR), which regulates DNA replication and RNA transcription. The aim of this study was to characterize BKV NCCR-variants in kidney biopsies and urine samples from renal-transplant patients and to see whether there is any association between NCCR variability and BKV-nephropathy. Kidney biopsies and urine samples were examined from 11 patients with elevated serum creatinine and >5,000 genomic BKV copies per ml of urine. BKV-nephropathy was diagnosed in seven patients. Using PCR, BKV NCCR was amplified from urine from all BKV-nephropathy patients. The dominant NCCR corresponded to the archetype (WWT). In addition, a total of 14 non-archetype NCCR-variants were detected. Thirteen of these NCCR-variants were found in urine from one single BKV-nephropathy patient also suffering from hepatitis C. The NCCR of BKV was amplified from kidney biopsies of six BKVnephropathy patients. Three patients demonstrated WWT NCCR, while three other patients harbored rearranged NCCR variants. The WWT NCCR was also detected in urine from control patients, except for one patient who harbored two non-archetypal NCCR variants. However, these variants were not resulting from complex rearrangements but instead had a linear NCCR anatomy with deletion(s) in the P-block. No BKV DNA was detected in biopsies from control patients. The results indicate that rearranged BKV NCCR is associated with BKV-nephropathy.

There is substantial variability in ovarian response to exogenous gonadotrophins in women undergoing ovarian stimulation for IVF. Genetic variation in signalling pathways of the ovary may influence ovarian stimulation outcome. One previous study showed an association between single nucleotide polymorphisms (SNP) in the gene for bone morphogenetic protein 15 (BMP15) and ovarian hyperstimulation syndrome (OHSS). This article presents a retrospective case-controlled genetic-association study designed to test the association between SNP in the BMP15 gene and two clinically important outcomes of ovarian stimulation: low and high response. Blood samples from 53 high responders, 38 low responders and 100 controls were analysed for five SNP of interest. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by a multivariate logistic regression model. We found an association between the BMP15 -9G allele and high response to ovarian stimulation (OR=2.7, 95% CI=1.3-5.7). This association confirms previous findings in a different population and strengthens the case for an association between this SNP and ovarian stimulation outcome.

There is substantial variability in ovarian response to exogenous gonadotrophins in women undergoing ovarian stimulation for IVF. Genetic variation in signalling pathways of the ovary could influence ovarian stimulation outcome. Studies have shown a correlation between the serum concentration of anti-Müllerian hormone (AMH) and ovarian stimulation outcome. This paper present a retrospective case-controlled genetic association study designed to test the association between single nucleotide polymorphisms (SNP) in the AMH signalling pathway and two clinically important outcomes of ovarian stimulation: low and high response. Blood samples from 53 high responders, 38 low responders and 100 controls were analysed for eight SNP of interest. Odds ratios and 95% confidence intervals were estimated by a binary logistic regression model adjusting for age and body mass index. As far as is known, this is the first report on the influence of these SNP, present in approximately 19% of women, on ovarian stimulation outcome. No statistically significant association was found between any of the SNP studied and high or low response to ovarian stimulation. It seems unnecessary to detect these SNP when applying the serum concentration of AMH as a predictor of ovarian response to stimulation. Many infertile couples are treated by IVF. Part of this treatment is to pharmacologically stimulate the ovaries to develop many oocytes simultaneously. This process is called ovarian stimulation. Some women respond either too little (low responders) or too much (high responders) to ovarian stimulation. Both these situations are unfavourable to the woman. This study evaluates whether these chances of having one of these two outcomes of ovarian stimulationare influenced by variation in the gene for anti-Müllerian hormone (AMH) or its receptor. This is done by taking blood samples from three groups of patients: low responders, high responders and controls with a normal response. These blood samples were analysed to see if the variation in the genes for AMH or its receptor were different in the three groups. They were not, and so we conclude that the genetic variation that exists in the AMH and receptor signalling pathway is not a major determinant of ovarian stimulation outcome.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5′ end and 3′ extension of precursor‐U8. There was no obvious genotype–phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3′ end processing of precursor‐U8.