SDHA secondary findings in germline testing: counseling and surveillance considerations.

This commentary explores the complexities faced by clinicians when encountering a secondary SDHA pathogenic variant (PV) in patients without a personal or family history of SDHA-related tumors. The increasing use of germline multi-gene panel testing has led to a rise in such secondary findings, necessitating a nuanced approach to counseling, surveillance, and decision-making. We aim to discuss the current data surrounding the penetrance of SDHA PVs, the spectrum of screening guidelines, recommendations for educating individuals and families about their secondary findings, and the need for future research to optimize care for these individuals. Practical recommendations for clinicians dealing with patients with secondary SDHA findings include acknowledging the limitations of existing guidelines, fostering shared decision-making, and considering specialist referrals. Overall, the evolving landscape of SDHA penetrance data warrants ongoing reassessment of surveillance approaches.

Characterizing the function of EPB41L4A in the predisposition to papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most common histotype of thyroid carcinoma. The heritability of PTC is high compared to other cancers, but its underlying causes are unknown. A recent genome-wide association study revealed the association of a variant at the 5q22 locus, rs73227498, with PTC predisposition. We report that rs17134155, a variant in high linkage disequilibrium with rs73227498, is located in an enhancer region downstream of coding transcripts of EPB41L4A. Rs17134155 showed significant enhancer activity in luciferase assays, and haplotypes containing the protective allele of this variant conferred a significantly lower risk of PTC. While the index SNP, rs73227498, acted as a significant cis-eQTL for expression of EPB41L4A, rs17134155 was a significant cis-sQTL for the alternative splicing of a non-coding transcript of EPB41L4A, called EPB41L4A-203. We also performed knockdown of EPB41L4A followed by microarray analysis. Some of the top differentially-expressed genes were represented among regulators of the WNT/ß-catenin signaling pathway. Our results indicate that an enhancer region at 5q22 regulates the expression and splicing of EPB41L4A transcripts. We also provide evidence that EPB41L4A expression is involved in regulating growth and differentiation pathways, suggesting that decreased expression of EPB41L4A is a mechanism in the predisposition to PTC.

Variants in LRRC34 reveal distinct mechanisms for predisposition to papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) demonstrates high heritability and a low somatic mutation burden relative to other cancers. Therefore, the genetic risk predisposing to PTC is likely due to a combination of low penetrance variants. A recent genome-wide association study revealed the association of PTC with a missense variant, rs6793295, at 3q26 in a gene called Leucine Repeat Rich Containing 34 (LRRC34). METHODS: We report the mechanisms of PTC risk at 3q26 using a combination of overexpression, mass spectroscopy, knockdown, transcriptome profiling, migration assays and genetic analysis. RESULTS: We observed differential binding of wild-type and missense LRRC34 to RANBP1. Overexpression of missense LRRC34 reduced RanGTP levels and increased apoptosis. We also identified a second linkage disequilibrium (LD) block upstream of LRRC34 containing regulatory variants with allele-specific expression. Transcriptome profiling of LRRC34 knockdown cells showed changes in genes involved with cellular movement. LRRC34 knockdown reduced the migration of thyroid cancer cell lines. Lastly, we assessed the relative contribution of PTC risk from each locus using haplotype analysis. CONCLUSIONS: Our study demonstrates two separate mechanisms, one in G protein signalling and the other in transcriptional control, dictating PTC risk at 3q26 using both biochemical and genetic techniques.

Microsatellite Instability Occurs in a Subset of Follicular Thyroid Cancers.

BACKGROUND: Inactivation of DNA mismatch repair (MMR) and the resulting microsatellite instability (MSI) are frequently observed in endometrial, stomach, and colorectal cancers, as well as more rarely in other solid tumor types. The prevalence of MSI in thyroid cancer has not been explored in depth, although recent studies utilizing data from large cancer sequencing efforts such as The Cancer Genome Atlas indicate that MSI is absent or at least very rare in the most common and most well studied histologic subtype, papillary thyroid carcinoma. This study aimed to determine the prevalence of MSI in thyroid cancer by using a large series comprising all major histological subtypes. METHODS: A total of 485 thyroid cancer patients were screened for MSI/MMR deficiency, including all major histologic subtypes (195 papillary thyroid carcinoma, 156 follicular thyroid carcinoma [FTC], 50 anaplastic thyroid carcinoma, 65 medullary thyroid carcinoma, and 17 poorly differentiated thyroid carcinomas) by using a combination of polymerase chain reaction-based detection, immunohistochemistry, and next-generation sequencing. RESULTS: A total of four tumors were MSI-high and had loss of MMR protein expression, all of which were from FTC patients. Whole-exome sequencing was performed on two MSI-high FTCs and revealed a hemizygous loss of function mutation in MSH2 in one tumor. CONCLUSIONS: Based on these data, it is estimated that the overall prevalence of MSI in FTC is 2.5%, and MSI is either entirely absent or rare in other histology subtypes of thyroid carcinoma. These findings highlight the importance of testing for MSI in FTC.

Neurotransmitter abnormalities and response to supplementation in SPG11.

OBJECTIVE: To report the detection of secondary neurotransmitter abnormalities in a group of SPG11 patients and describe treatment with l-dopa/carbidopa and sapropterin. DESIGN: Case reports. SETTING: National Institutes of Health in the Undiagnosed Disease Program; Children's National Medical Center in the Myelin Disorders Bioregistry Program. PATIENTS: Four SPG11 patients with a clinical picture of progressive spastic paraparesis complicated by extrapyramidal symptoms and maculopathy. INTERVENTIONS: L-Dopa/carbidopa and sapropterin. RESULTS: 3/4 patients presented secondary neurotransmitter abnormalities; 4/4 partially responded to L-dopa as well as sapropterin. CONCLUSIONS: In the SPG11 patient with extrapyramidal symptoms, a trial of L-dopa/carbidopa and sapropterin and/or evaluation of cerebrospinal fluid neurotransmitters should be considered.

Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2.

We have identified a recurrent de novo pericentromeric deletion in 16p11.2-p12.2 in four individuals with developmental disabilities by microarray-based comparative genomic hybridization analysis. The identification of common clinical features in these four individuals along with the characterization of complex segmental duplications flanking the deletion regions suggests that nonallelic homologous recombination mediated these rearrangements and that deletions in 16p11.2-p12.2 constitute a previously undescribed syndrome.