GGC Repeat Expansion in the NOTCH2NLC Gene Is Associated With a Phenotype of Predominant Motor–Sensory and Autonomic Neuropathy

There is still a considerable proportion of patients with inherited peripheral neuropathy (IPN) whose pathogenic genes are unknown. This study was intended to investigate whether the GGC repeat expansion in the NOTCH2NLC is presented in some patients with IPN. A total of 142 unrelated mainland Chinese patients with highly suspected diagnosis of IPN without any known causative gene were recruited. Repeat-primed polymerase chain reaction (RP-PCR) was performed to screen GGC repeat expansion in NOTCH2NLC, followed by fluorescence amplicon length analysis-PCR (AL-PCR) to determine the GGC repeat size. Detailed clinical data as well as nerve, muscle, and skin biopsy were reviewed and analyzed in the NOTCH2NLC-related IPN patients. In total, five of the 142 patients (3.52%) were found to have pathogenic GGC expansion in NOTCH2NLC, with repeat size ranging from 126 to 206 repeats. All the NOTCH2NLC-related IPN patients presented with adult-onset motor–sensory and autonomic neuropathy that predominantly affected the motor component of peripheral nerves. While tremor and irritating dry cough were noted in four-fifths of the patients, no other signs of the central nervous system were presented. Electrophysiological studies revealed both demyelinating and axonal changes of polyneuropathy that were more severe in lower limbs and asymmetrically in upper limbs. Sural nerve pathology was characterized by multiple fibers with thin myelination, indicating a predominant demyelinating process. Muscle pathology was consistent with neuropathic changes. P62-positive intranuclear inclusions were observed in nerve, skin, and muscle tissues. Our study has demonstrated that GGC expansion in NOTCH2NLC is associated with IPN presenting as predominant motor–sensory and autonomic neuropathy, which expands the phenotype of the NOTCH2NLC-related repeat expansion spectrum. Screening of GGC repeat expansions in the NOTCH2NLC should be considered in patients presenting with peripheral neuropathy with tremor and irritating dry cough.

Tandem Repeats in Bacillus: Unique Features and Taxonomic Distribution

Little is known about DNA tandem repeats across prokaryotes. We have recently described an enigmatic group of tandem repeats in bacterial genomes with a constant repeat size but variable sequence. These findings strongly suggest that tandem repeat size in some bacteria is under strong selective constraints. Here, we extend these studies and describe tandem repeats in a large set of Bacillus. Some species have very few repeats, while other species have a large number. Most tandem repeats have repeats with a constant size (either 52 or 20–21 nt), but a variable sequence. We characterize in detail these intriguing tandem repeats. Individual species have several families of tandem repeats with the same repeat length and different sequence. This result is in strong contrast with eukaryotes, where tandem repeats of many sizes are found in any species. We discuss the possibility that they are transcribed as small RNA molecules. They may also be involved in the stabilization of the nucleoid through interaction with proteins. We also show that the distribution of tandem repeats in different species has a taxonomic significance. The data we present for all tandem repeats and their families in these bacterial species will be useful for further genomic studies.

Refining the risk for fragile X–associated primary ovarian insufficiency (FXPOI) by FMR1 CGG repeat size

Purpose Approximately 20–30% of women with an FMR1 premutation experience fragile X–associated primary ovarian insufficiency (FXPOI); however, current risk estimates based on repeat size only identify women with the midrange of repeats to be at the highest risk. Methods To better understand the risk by repeat size, we collected self-reported reproductive histories on 1,668 women and divided them into high-resolution repeat size bins of ~5 CGG repeats to determine a more accurate risk for FXPOI in relation to CGG repeat length. Results As previously reported, women with 70–100 CGG repeats were at the highest risk for FXPOI using various statistical models to compare average age at menopause and risk of FXPOI, with women with 85–89 repeats being at the highest risk. Importantly, women with <65 repeats or >120 repeats did not have a significantly increased risk for FXPOI compared to women with <45 repeats. Conclusion Using a large cross-section study on 1,668 women, we have provided more personalized risk assessment for FXPOI using high-resolution repeat size bins. Understanding the variability in risk has important implications for family planning and overall health among women with a premutation.

The FRAXA and FRAXE allele repeat size of boys from the Avon Longitudinal Study of Parents and Children (ALSPAC)

The FRAXA and FRAXE alleles of the FMR1 and FMR2 genes located on the X chromosome contain varying numbers of trinucleotide repeats. Large numbers of repeats at FRAXA (full mutations) manifest as Fragile X syndrome, associated with mental impairment that affects males more severely. In this paper, we present the dataset of frequencies of FRAXA and FRAXE repeat size extracted from DNA samples collected from boys enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). DNA data were extracted from samples collected in ALSPAC clinics from several types of samples: cord blood, venepuncture blood taken at 43 months, 61 months, seven years or nine years. The DNA was amplified at FRAXA and FRAXE using fluorescent PCR in the Wessex Regional Genetics Laboratory, Salisbury District Hospital. The mean repeat size for FRAXA is 28.92 (S.D. 5.44), the median 30 and the range 8 to 68. There were particularly high numbers of boys with repeat sizes of 20 (10.67%) and 23 (7.35%). The mean repeat size for FRAXE is 17.41 (S.D. 3.94), with median of 16 and range of 0 to 61. There is a relatively high degree of variation of the FRAXA repeat size particularly and we suggest the extensive data available from the ALSPAC study opens up areas of research into understanding phenotypes associated with relatively unexplored repeat sizes. This could be particularly interesting for the lower repeat sizes occurring with high frequency at FRAXA in this population. As the data can be linked to exposures and phenotypes, it will provide a resource for researchers worldwide.

The FRAXA and FRAXE allele repeat size of boys from the Avon Longitudinal Study of Parents and Children (ALSPAC)

The FRAXA and FRAXE alleles of the FMR1 and FMR2 genes located on the X chromosome contain varying numbers of trinucleotide repeats. Large numbers of repeats at FRAXA (full mutations) manifest as Fragile X syndrome, associated with mental impairment that affects males more severely. In this paper, we present the dataset of frequencies of FRAXA and FRAXE repeat size extracted from DNA samples collected from boys enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). DNA data were extracted from samples collected in ALSPAC clinics from several types of samples: cord blood, venepuncture blood taken at 43 months, 61 months, seven years or nine years. The DNA was amplified at FRAXA and FRAXE using fluorescent PCR in the Wessex Regional Genetics Laboratory, Salisbury District Hospital. The mean repeat size for FRAXA is 28.92 (S.D. 5.44), the median 30 and the range 8 to 68. There were particularly high numbers of boys with repeat sizes of 20 (10.67%) and 23 (7.35%). The mean repeat size for FRAXE is 17.41 (S.D. 3.94), with median of 16 and range of 0 to 61. There is a relatively high degree of variation of the FRAXA repeat size particularly and we suggest the extensive data available from the ALSPAC study opens up areas of research into understanding phenotypes associated with relatively unexplored repeat sizes. This could be particularly interesting for the lower repeat sizes occurring with high frequency at FRAXA in this population. As the data can be linked to exposures and phenotypes, it will provide a resource for researchers worldwide.

FSHD1 and FSHD2 form a disease continuum

ObjectiveTo compare the clinical features of patients showing a classical phenotype of facioscapulohumeral muscular dystrophy (FSHD) with genetic and epigenetic characteristics of the FSHD1 and FSHD2 loci D4Z4 and SMCHD1.MethodsThis is a national multicenter cohort study. We measured motor strength, motor function, and disease severity by manual muscle testing sumscore, Brooke and Vignos scores, clinical severity score (CSS), and age-corrected CSS, respectively. We correlated these scores with genetic (D4Z4 repeat size and haplotype; SMCHD1 variant status) and epigenetic (D4Z4 methylation) parameters.ResultsWe included 103 patients: 54 men and 49 women. Among them, we identified 64 patients with FSHD1 and 20 patients with FSHD2. Seven patients had genetic and epigenetic characteristics of FSHD1 and FSHD2, all carrying repeats of 9–10 D4Z4 repeat units (RU) and a pathogenic SMCHD1 variant. In the remaining patients, FSHD was genetically excluded or remained unconfirmed. All clinically affected SMCHD1 mutation carriers had a D4Z4 repeat of 9–16 RU on a disease permissive 4qA haplotype. These patients are significantly more severely affected by all clinical scales when compared to patients with FSHD1 with upper-sized FSHD1 alleles (8–10 RU).ConclusionThe overlap between FSHD1 and FSHD2 patients in the 9–10 D4Z4 RU range suggests that FSHD1 and FSHD2 form a disease continuum. The previously established repeat size threshold for FSHD1 (1–10 RU) and FSHD2 (11–20 RU) needs to be reconsidered.Clinicaltrials.gov identifierNCT01970735.