A hereditary spastic paraplegia predominant phenotype caused by variants in the NEFL gene.

INTRODUCTION: This study reports a large series of patients with a clinical picture dominated by spastic paraplegia in whom variants in the NEFL gene, a known cause for Charcot-Marie-Tooth disease, were identified. METHODS: Index patients referred for a suspicion of hereditary spastic paraplegia (HSP) were clinically assessed and genetic analysis by next-generation sequencing was undertaken. Additional family members were clinically examined and subjected to targeted testing. RESULTS: We identified two different heterozygous dominant variants in the NEFL gene in 25 patients from 14 families. Most of them (21/25) had a clinical diagnosis of HSP, often with a concomitant clinical diagnosis of polyneuropathy (16/21). Two patients were identified with a polyneuropathy with a pyramidal reflex pattern, but without spasticity. Two patients had isolated polyneuropathy. Out of the 21 patients with a diagnosis of HSP, two had co-occurring cerebellar signs. The c.262A > C p.(Thr88Pro) variant was detected in 13 families. Genealogical analysis showed shared ancestors or a similar geographical origin in 12, suggesting a founder effect. The other variant, c.296A > C p.(Asp99Ala), was found in only one family, in which limited segregation analysis could be performed. DISCUSSION: Variants in the NEFL gene can cause HSP, with or without co-existing polyneuropathy, and should be included in diagnostic testing strategies for HSP patients.

Prevalence of germline mutations in the spindle assembly checkpoint gene BUB1B in individuals with early-onset colorectal cancer.

Germline mutations in BUB1B, encoding BUBR1, one of the crucial components of the spindle assembly checkpoint (SAC), have been shown to cause variable phenotypes, including the recessive mosaic variegated aneuploidy (MVA) syndrome, which predisposes to cancer. Reduced levels of the wild-type BUBR1 protein have been linked to the development of gastrointestinal neoplasms. To determine whether mutations in BUB1B are enriched in individuals with colorectal cancer (CRC), we performed amplicon-based targeted next-generation sequencing of BUB1B on germline DNA of 192 individuals with early-onset CRC (≤50 years). None of the individuals was found to be homozygous or compound heterozygous for mutations in BUB1B. However, we did identify two rare heterozygous variants, p.Glu390del and p.Cys945Tyr, in patients who developed CRC at the ages of 41 and 43 years, respectively. Both variants were shown not to affect BUBR1 protein expression levels and protein localization. Since the p.Glu390del variant is located in the BUB3-binding domain, we also performed immunoprecipitation to examine whether this variant affects the binding of BUB1 or BUB3 to BUBR1 but, compared to wild-type BUBR1, no difference was observed. Our data suggest that mutations in BUB1B do not occur frequently in the germline of individuals with CRC and that BUB1B unlikely plays a major role in the predisposition to early-onset CRC. Whether carriers of pathogenic BUB1B mutations, such as the parents of MVA syndrome patients, have an increased risk for cancer remains of interest, as studies in mice have suggested that haploinsufficiency of BUB1B may cause an increase in carcinogen-induced tumors. © 2016 Wiley Periodicals, Inc.

Focusing on patient needs and preferences may improve genetic counseling for colorectal cancer.

During cancer genetic counseling, different items which counselors consider important are discussed. However, relatively little empirical evidence exists regarding the needs and preferences of counselees. In this study needs and preferences were assessed from counselees with a personal and/or family history of colorectal cancer (CRC), who were referred for genetic counseling regarding CRC. They received a slightly modified version of the QUOTE-GENE(ca) questionnaire prior to their first visit to the Hereditary Cancer Clinic. Response rate was 60 % (48/80 participants). Counselees rated the importance of 45 items assessing their needs and preferences regarding the content and process of genetic counseling. Participants rated the items regarding discussion of information about their familial CRC risk (100 %) and preventive options (98 %) as important or very important. Fewer participants rated items concerning general information on genetics as important. Sensitive communication during counseling was considered very important by a large percentage of counselees. Generally, no major differences were seen between participants in relation to individual characteristics. Our data suggest that focusing on familial CRC risk and surveillance options, in combination with sensitive communication may lead to better satisfaction with genetic counseling.