A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies.

POT1 (Protection of Telomeres 1) is a key component of the six-membered shelterin complex that plays a critical role in telomere protection and length regulation. Germline variants in the POT1 gene have been implicated in predisposition to cancer, primarily to melanoma and chronic lymphocytic leukemia (CLL). We report the identification of POT1 p.(I78T), previously ranked with conflicting interpretations of pathogenicity, as a founder pathogenic variant among Ashkenazi Jews (AJs) and describe its unique clinical landscape. A directed database search was conducted for individuals referred for genetic counselling from 2018 to 2023. Demographic, clinical, genetic, and pathological data were collected and analyzed. Eleven carriers, 25 to 67 years old, from ten apparently unrelated families were identified. Carriers had a total of 30 primary malignancies (range 1-6); nine carriers (82%) had recurrent melanoma between the ages of 25 and 63 years, three carriers (27%) had desmoid tumors, three (27%) had papillary thyroid cancer (PTC), and five women (63% of female carriers) had breast cancer between the ages of 44 and 67 years. Additional tumors included CLL; sarcomas; endocrine tumors; prostate, urinary, and colorectal cancers; and colonic polyps. A review of a local exome database yielded an allelic frequency of the variant of 0.06% among all ethnicities and of 0.25% in AJs. A shared haplotype was found in all carriers tested. POT1 p.(I78T) is a founder disease-causing variant associated with early-onset melanoma and additional various solid malignancies with a high tumor burden. We advocate testing for this variant in high-risk patients of AJ descent. The inclusion of POT1 in germline panels for various types of cancer is warranted.

[HOW SIMPLE IS "SIMPLE" GENETIC COUNSELING?]

INTRODUCTION: Genetic counselors are often compared with other medical professionals in terms of productivity, based on the number of patients seen and the time required for each patient. Prenatal genetic counseling before amniocentesis in uneventful pregnancies is considered to be a "simple" counseling, with potentially less time required for each patient. Thus, in some medical centers the duration of such consultations is limited to provide only the basic explanation without detailed collection of personal and family history, while in others the explanation is given to several patients together. AIMS: To assess the need for extended genetic counseling during supposedly "simple" genetic consultations before amniocentesis. METHODS: Data was collected from January 2018 until August 2020 of all patients undergoing genetic counseling before amniocentesis due to advanced maternal age, abnormal biochemical screening, or without medical indication. The consultations were given by four genetic counselors and two medical geneticists. The need for extended genetic counseling was evaluated based on pedigree and the discussion summaries and recommendations noted in genetic counseling summaries. RESULTS: Of the 1085 relevant counseling appointments, 657 (60.5%) required additional explanation beyond the basic consultation. The reasons for extended counseling included medical disorders of the woman or spouse (21.2%), carrier state for autosomal recessive diseases (18.6%), diagnosed or suspected genetic conditions of a child or previous pregnancy (9.6%), or medical disorders in the extended family (79.1%). In 31.0% of patients, recommended carrier screening tests were recommended or added. In 32.3% of cases, only one extra subject was counseled, in 16.3% two subjects, and in 5%, three subjects or more. The additional explanations were estimated as short (up to 5 minutes) in 36.9% of the cases, intermediate (5 to 15 minutes) in 59.9%, and long (over 15 minutes) in 2.6% of cases. The consultation's duration was not affected from it being a first meeting or a recurrent consultation. CONCLUSIONS: The need for further explanation was demonstrated in over 60% of genetic consultations, performed prior to amniocentesis due to supposedly "simple" indication. DISCUSSION: This fact reflects the importance of formal genetic counseling even in cases of seemingly simple indications, with an emphasis on detailed personal and family history, dedicating sufficient time to the counseling itself. Alternatively, it is important to exercise extra caution when conducting a short explanatory conversation prior to amniocentesis, including detailed questionnaires and the patient's signature on the possible limitations of such explanations.

SMYD1 is the underlying gene for the AnWj-negative blood group phenotype.

BACKGROUND: AnWj is a high-incidence blood group antigen associated with three clinical disorders: lymphoid malignancies, immunologic disorders, and autoimmune hemolytic anemia. The aim of this study was to determine the genetic basis of an inherited AnWj-negative phenotype. METHODS: We identified a consanguineous family with two AnWj-negative siblings and 4 additional AnWj-negative individuals without known familial relationship to the index family. We performed exome sequencing in search for rare homozygous variants shared by the two AnWj-negative siblings of the index family and searched for these variants in the four non-related AnWj-negative individuals. RESULTS: Exome sequencing revealed seven candidate genes that showed complete segregation in the index family and for which the two AnWj-negative siblings were homozygous. However, the four additional non-related AnWj-negative subjects were homozygous for only one of these variants, rs114851602 (R320Q) in the SMYD1 gene. Considering the frequency of the minor allele, the chance of randomly finding 4 consecutive such individuals is 2.56 × 10-18 . CONCLUSION: We present genetic and statistical evidence that the R320Q substitution in SMYD1 underlies an inherited form of the AnWj-negative blood group phenotype. The mechanism by which the mutation leads to this phenotype remains to be determined.