Founder Pathogenic Variant Research Articles

Breast Cancer Phenotype Associated With Li-Fraumeni Syndrome: A Brazilian Cohort Enriched by TP53 p.R337H Carriers.

Breast cancer (BC) is the most prevalent malignancy in women with Li-Fraumeni syndrome (LFS). The literature on BC in LFS is limited due to its rarity worldwide. A TP53 founder pathogenic variant (c.1010G>A; p.R337H) is responsible for the higher prevalence of this syndrome among women of Brazilian ancestry.PurposeThe aim of the study was to describe the BC phenotype expressed by Brazilian female LFS carriers and compare the data between p.R337H and other TP53 germline pathogenic/likely pathogenic variants (non-p.R337H carriers).MethodsWe searched for cases of TP53 germline pathogenic/likely pathogenic variant carriers affected by BC included between 2015 and 2020 in the BLiSS (Brazilian Li-Fraumeni Study) registry at the Sírio-Libanês Hospital.ResultsAmong 163 adult female carriers from the registry, 91 (56%) had received a BC diagnosis, including 72 p.R337H carriers. BC was the first cancer diagnosed in 90% of cases. Early onset BC (age ≤45 years) was diagnosed in 78.2% of cases (11.5% <31 years; 66.7% 31–45 years; 21.8% >45 years). The median age of BC diagnosis for p.R337H carriers was 39.5 years (range 20–69 years) compared to 34 years (range 21–63 years) for non-p.R337H carriers (p = 0.009). In total, 104 breast tumors were observed in 87 women. Bilateral BC was observed in 29.3% of cases. Histology was available for 96 tumors, comprising 69 invasive breast carcinomas, which were mostly invasive ductal carcinomas (95.6%), 25 ductal in situ carcinomas and 2 soft-tissue sarcomas. Overall, 90.5% of invasive breast carcinomas were hormone receptor (HR)-positive, 39.5% were human epidermal growth factor receptor 2 (HER2)-positive, and 32.8% showed HR and HER2 co-expression. In addition, 55.4% of patients opted for contralateral prophylactic mastectomy after a first BC diagnosis. There were no significant differences in the risk of developing contralateral BC or in the immunohistochemical profile between p.R337H and non-p.R337H groups.ConclusionsThe expressed phenotype of p.R337H is similar to that of other TP53 pathogenic/likely pathogenic variants, except for an average older age at the onset of disease; however, this is still younger than the general population.

Common founder BRCA2 pathogenic variants and breast cancer characteristics in Ethiopian Jews

BRCA1/2 founder pathogenic variants (PVs) occur in various populations, but data on the mutational spectrum in Africans are limited. We examined BRCA1/2 PVs in breast cancer patients of Ethiopian Jewish (EJ) origin. We retrospectively analyzed BRCA1/2 test results and clinical features of EJ breast cancer patients from seven medical institutions. We obtained heterozygote carrier rates in affected individuals from the laboratories of the largest Israeli HMO (Clalit). Population carrier frequency was determined in EJ controls. We identified three recurrent BRCA2 PVs in 11 EJ breast cancer patients (9 females, 2 males): c.7579delG, c.5159C > A, and c.9693delA. Only c.5159C > A was previously reported in Africans. In women, mean age at diagnosis was 35.7y; 8/9 were diagnosed with advanced disease. All tumors were invasive, 4/9 were triple negative. Only 3/11 carriers had relevant family history. Carrier rate in high-risk breast cancer patients was 11% (3/28; 95%CI [2.3%, 28.2%]). Combined carrier rate among controls was 1.8% (5/280; 95%CI [0.6%, 4.1%]). EJs harbor 3 recurrent BRCA2 PVs presenting with relatively severe breast cancer morbidity. Combined with the high BRCA2 carrier rate in the EJ population, these findings merit increasing awareness in this community and suggest that a culturally adapted population screening approach may be warranted.

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG.

Fanconi anemia (FA) is a rare genetic disorder caused by pathogenic variants (PV) in at least 22 genes, which cooperate in the Fanconi anemia/Breast Cancer (FA/BRCA) pathway to maintain genome stability. PV in FANCA, FANCC, and FANCG account for most cases (~90%). This study evaluated the chromosomal, molecular, and physical phenotypic findings of a novel founder FANCG PV, identified in three patients with FA from the Mixe community of Oaxaca, Mexico. All patients presented chromosomal instability and a homozygous PV, FANCG: c.511-3_511-2delCA, identified by next-generation sequencing analysis. Bioinformatic predictions suggest that this deletion disrupts a splice acceptor site promoting the exon 5 skipping. Analysis of Cytoscan 750 K arrays for haplotyping and global ancestry supported the Mexican origin and founder effect of the variant, reaffirming the high frequency of founder PV in FANCG. The degree of bone marrow failure and physical findings (described through the acronyms VACTERL-H and PHENOS) were used to depict the phenotype of the patients. Despite having a similar frequency of chromosomal aberrations and genetic constitution, the phenotype showed a wide spectrum of severity. The identification of a founder PV could help for a systematic and accurate genetic screening of patients with FA suspicion in this population.

Abstract P2-09-13: Is there a male breast cancer cluster region in the BRCA2 gene?

Abstract Background: The location of the variant in the BRCA2 gene may have a role on the differential risk of hereditary breast-ovarian cancer (HBOC) families. Three Breast Cancer Cluster Regions (BCCR) have been previously identified in BRCA2: BCCR1- c.1-c.596; BCCR1’- c.772-c.1806; BCCR2- c.7394-c.8904. BCCR1 includes the Portuguese founder pathogenic variant (c.156_157insAlu), which explains up to 1/3 of hereditary breast cancer. As previously described one of the associated phenotypes of c.156_157insAlu is male breast cancer (MBC). We analyzed all MBC BRCA2 families registered in our program searching for a possible association between variant location in the BRCA2 gene and MBC. Methodology: This is a Portuguese, single-center, cross-sectional study, including all families identified with a pathogenic variant in the BRCA2 gene between December 1999 and December 2019. BRCA2 families with MBC cases were selected for further analysis including gene mapping of identified variants. The study was approved by our center’s IRB/IEC. Results: Of a total of 452 confirmed BRCA1/2 families, 285 were diagnosed with a BRCA2 pathogenic variant. Review of these 285 genograms identified 57 families with MBC in their phenotype, including 62 men diagnosed with 69 breast cancer cases (7 bilateral). Twenty-nine (47%) MBC patients were confirmed to be carriers of a BRCA2 pathogenic variant (26 tested, 3 obligate carriers); the others were considered to be probable BRCA2 carriers based on family analysis. Besides MBC other BRCA2-associated cancers were identified in these families: female breast cancer (FBC, 82%), prostate cancer (35%), gastric cancer (18%), pancreatic cancer (16%) and ovarian cancer (12%). In 6 (2%) BRCA2 families, breast cancer was exclusively diagnosed in men.Eighteen (32%) MBC patients were diagnosed with other cancers: 9 prostate, 5 colorectal, 3 gastric, 2 kidney, 1 bladder, 1 pancreatic and 1 central nervous system.The most commonly identified variant was the c.156_157insAlu (24, 38.7%), followed by c.9097dupA (6.5%), c.793+1G&amp;gt;A (4.8%) and c.2808_2811delACAA (4.8%).Thirty-six (63%) of the identified variants were located on the previously described BCCR (46% in BCCR1, 11% in BCCR1’ and 7% in BCCR2). The remaining variants were located in other areas of the BRCA2 gene: 12% closer to BRCA2 3’ terminal (exons 23-25); 1.8% in exon 8; and the remaining scattered through exon 11 (in 14% of cases in regions previously described as associated to ovarian cancer). The proportion of BCCR variants was significantly lower on confirmed carriers compared to probable carriers (48.3% vs 78.6%, chi-square p=0.018), due to a higher proportion of variants located on exons 23-25 (17.2% vs 7.1%) and on exon 11 (31% vs 14.2%). Approximately half of the bilateral MBC cases (57% of the total sample, 50% of the confirmed carriers) were associated with BCCR variants. Conclusion: Our data suggest that BCCR1 may be a male breast cancer cluster region (MBCCR). The clustering of confirmed MBC distal to BCCR2, closer to the BRCA2 3’ terminal, raises the possibility of a specific MBCCR, and warrants further research. Citation Format: Pedro Simões, Teresa Duarte, Joana Parreira, Ana Luís, Sandra Bento, Sofia Fragoso, Sidónia Santos, Fátima Vaz, Saudade André. Is there a male breast cancer cluster region in the BRCA2 gene? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-13.

Targeted BRCA1/2 population screening among Ashkenazi Jewish individuals using a web-enabled medical model: An observational cohort study

PurposeThis study aimed to evaluate uptake and follow-up using internet-assisted population genetic testing (GT) for BRCA1/2 Ashkenazi Jewish founder pathogenic variants (AJPVs). MethodsAcross 4 cities in the United States, from December 2017 to March 2020, individuals aged ≥25 years with ≥1 Ashkenazi Jewish grandparent were offered enrollment. Participants consented and enrolled online with chatbot and video education, underwent BRCA1/2 AJPV GT, and chose to receive results from their primary care provider (PCP) or study staff. Surveys were conducted at baseline, at 12 weeks, and annually for 5 years. ResultsA total of 5193 participants enrolled and 4109 (79.1%) were tested (median age = 54, female = 77.1%). Upon enrollment, 35.1% of participants selected a PCP to disclose results, and 40.5% of PCPs agreed. Of those tested, 138 (3.4%) were AJPV heterozygotes of whom 21 (15.2%) had no significant family history of cancer, whereas 86 (62.3%) had a known familial pathogenic variant. At 12 weeks, 85.5% of participants with AJPVs planned increased cancer screening; only 3.7% with negative results and a significant family history reported further testing. ConclusionAlthough continued follow-up is needed, internet-enabled outreach can expand access to targeted GT using a medical model. Observed challenges for population genetic screening efforts include recruitment barriers, improving PCP engagement, and increasing uptake of additional testing when indicated.

Re-evaluating cancer risks associated with the CHEK2 p.Ser428Phe Ashkenazi Jewish founder pathogenic variant.

A missense variant (p.Ser428Phe [S428F]) in the CHEK2 gene is reportedly associated with a 2-3 fold increase in breast cancer risk in Ashkenazi Jews. This study aimed to re-evaluate cancer risks conferred by the CHEK2 S428F variant in Ashkenazi Jews. De-identified data from CHEK2 S428F variant carriers sequenced with multigene panels were analyzed. Overall, 486/341,531 (0.14%) cases of all ethnicities diagnosed with any cancer type were CHEK2 S428F carriers, of whom 243/9980 self-identified as Ashkenazi Jews and carried this risk variant only. Compared with ethnically matched non-cancer controls, across all cancer cases, this variant was not more prevalent (p = 0.271). Specifically, variant prevalence was not different in breast cancer cases compared with controls. Though the variant was shown to be enriched in pancreatic cancer cases (p = 0.008), sample size was small. The CHEK2 S428F variant was not overrepresented in Ashkenazi Jews with breast cancer and most other cancer types analyzed, except for pancreatic cancer, compared with ethnically matched non- cancer controls. These findings should prompt reevaluating ethnic-specific CHEK2 S428F cancer attributable risk.

Expanding on the phenotypic spectrum of Woodhouse-Sakati syndrome due to founder pathogenic variant in DCAF17: Report of 58 additional patients from Qatar and literature review.

Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive neuroendocrine and ectodermal disorder caused by variants in the DCAF17 gene. In Qatar, the c.436delC variant has been reported as a possible founder pathogenic variant with striking phenotypic heterogeneity. In this retrospective study, we report on the clinical and molecular characteristics of additional 58 additional Qatari patients with WSS and compare them to international counterparts' findings. A total of 58 patients with WSS from 32 consanguineous families were identified. Ectodermal and endocrine (primary hypogonadism) manifestations were the most common presentations (100%), followed by diabetes mellitus (46%) and hypothyroidism (36%). Neurological manifestations were overlapping among patients with intellectual disability (ID) being the most common (75%), followed by sensorineural hearing loss (43%) and both ID and aggressive behavior (10%). Distinctive facial features were noted in all patients and extrapyramidal manifestations were uncommon (8.6%). This study is the largest to date on Qatari patients with WSS and highlights the high incidence and clinical heterogeneity of WSS in Qatar due to a founder variant c.436delC in the DCAF17 gene. Early suspicion of WSS among Qatari patients with hypogonadism and ID, even in the absence of other manifestations, would shorten the diagnostic odyssey, guide early and appropriate management, and avoid potential complications.

A Founder Pathogenic Variant of PPIB Unique to Chinese Population Causes Osteogenesis Imperfecta IX.

Background: Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility. PPIB pathogenic variants cause a perinatal lethal form of OI type IX. A limited number of pathogenic variants have been reported so far worldwide. Methods: We identified a rare pedigree whose phenotype was highly consistent with OI-IX. Exome sequencing was performed to uncover the causal variants. The variant pathogenicity was classified following the ACMG/AMP guidelines. The founder effect and the age of the variant were assessed. Results: We identified a homozygous missense variant c.509G > A/p.G170D in PPIB in an affected fetus. This variant is a Chinese-specific allele and can now be classified as pathogenic. We estimated the allele frequency (AF) of this variant to be 0.0000427 in a Chinese cohort involving 128,781 individuals. All patients and carriers shared a common haplotype, indicative of a founder effect. The estimated age of variant was 65,160 years. We further identified pathogenic variants of PPIB in gnomAD and ClinVar databases, the conserved estimation of OI type IX incidence to be 1/1,000,000 in Chinese population. Conclusion: We reported a founder pathogenic variant in PPIB specific to the Chinese population. We further provided our initial estimation of OI-IX disease incidence in China.

Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males

ObjectiveOne of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that MYBPC3 c.2149–1G>A...

Genetic Analysis of Archived Tumor Specimens for Hereditary Colorectal Cancer Syndromes in the Cajuns of Louisiana, a US Founder Population.

INTRODUCTION:The Louisiana Acadian region (population 1.2 million), home of the Cajuns, has among the highest US colorectal cancer (CRC) rates. Although Cajuns are a known genetic founder population, studies assessing for hereditary CRC have not been performed.METHODS:A retrospective review of 2 hospital cancer registries was performed to identify young (<55) Cajun CRC patients in Lafayette, Louisiana (the Acadian region population center), diagnosed from 2003 to 2016. Men were studied because of the higher likelihoods of retaining Cajun surnames for ancestry identification compared with women. Immunohistochemistry for mismatch repair proteins associated with the Lynch syndrome (LS) was performed on tumors. Germline sequencing was performed on adjacent normal tissue of these archived formalin-fixed paraffin-embedded surgical resection specimens for pathogenic variants underlying CRC-associated syndromes, including LS, familial adenomatous polyposis, and others.RESULTS:Of 9 young Cajuns, a germline analysis revealed LS in 2 (MLH1 frameshift, MLH1 missense pathogenic variants). Both had immunohistochemistry-deficient MLH1. Two others had the same adenomatous polyposis coli variant of unknown significance (2 algorithms predicting deleterious and probably damaging change), making this a potential familial adenomatous polyposis founder effect candidate.DISCUSSION:This is the first study assessing for hereditary CRC in a large US regional founder population. This small study did not identify clear Cajun founder pathogenic variants. However, larger studies are warranted, which could also help clarify the clinical significance of the adenomatous polyposis coli variant of unknown significance. This study is important because it demonstrates that a retrospective tumor analysis can be used to ascertain the prevalence of genetic susceptibility in specific populations.

Recurrent FAN1 p.W707X Pathogenic Variant Originating Before ad 1800 Underlies High Frequency of Karyomegalic Interstitial Nephritis in South Pacific Islands

Recurrent FAN1 p.W707X Pathogenic Variant Originating Before ad 1800 Underlies High Frequency of Karyomegalic Interstitial Nephritis in South Pacific Islands

A recurrent pathogenic BRCA2 exon 5-11 duplication in the Christian Arab population in Israel.

Germline pathogenic variants (PVs) in BRCA1/BRCA2 are well-established risk factors for breast cancer (BC) and/or ovarian cancer (OC). Founder PVs have been described in BRCA1/ BRCA2 in several genetic isolates. The Christian Arab population in the Middle East is a relatively isolated ethnic group, yet founder, or recurrent BRCA1/BRCA2 PVs have not been reported in this population. In this study we describe PVs detected in cancer susceptibility genes among a cohort of Christian Arabs from Israel. We reviewed patient records from the Oncogenetic clinic at Rambam Health Care Campus during the years 2013- mid 2020. Thirty-five unrelated Christian Arab patients, with personal or family history of BC and/or OC underwent BRCA1/BRCA2 (14/35) testing or cancer gene panel testing (21/35) as part of their diagnostic workup. Three clinically significant variants in BRCA2, CHEK2 and RAD51C were found in 7/35 patients (20%). A recurrent duplication of the BRCA2 genomic region, encompassing exons 5-10 and the 5' portion of exon 11, was found in 5/33 (15.2%) patients for whom copy number variants (CNVs) analysis was performed. We identified a recurrent pathogenic BRCA2 duplication in Christian Arab patients with a personal/ family history of BC and/or OC. Our findings emphasize the importance of inclusion of CNVs analysis in BRCA1/BRCA2 genetic testing, and specifically for Christian Arab patients suspected of hereditary BC and/or OC.

A Population-Based Study of Genes Previously Implicated in Breast Cancer

BackgroundPopulation-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.MethodsIn a population-based case–control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.ResultsPathogenic variants in 12 established breast cancer–predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor–negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor–positive breast cancer. Pathogenic variants in 16 candidate breast cancer–predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer.ConclusionsThis study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer–predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)

Analysis of Italian BRCA1/2 Pathogenic Variants Identifies a Private Spectrum in the Population from the Bergamo Province in Northern Italy.

Simple SummaryThe Italian population is characterized by a high genetic heterogeneity mostly due to its long history of migration and colonization and to its geographical conformation. Consistently, several BRCA1/2 pathogenic variants (PVs) have been reported to be recurrent or even founder in defined geographical areas including the Bergamo province in Northern Italy. In this study, we retrospectively analyzed the data from 1019 women affected with breast cancer with BRCA1/2 PVs. We compared the BRCA1/2 PVs spectrum found in the carrier individuals from the Bergamo province (BGP) with that of the general Italian population. We found that the majority of the BGP PVs had a local origin and remained confined to the BGP or to the surrounding Lombardy region. We also observed that the BGP BRCA1/2 PV spectrum is private and conserved comprising a smaller number of variants with an average higher frequency with respect to that of carrier individuals from the rest of Italy.Germline pathogenic variants (PVs) in the BRCA1 or BRCA2 genes cause high breast cancer risk. Recurrent or founder PVs have been described worldwide including some in the Bergamo province in Northern Italy. The aim of this study was to compare the BRCA1/2 PV spectra of the Bergamo and of the general Italian populations. We retrospectively identified at five Italian centers 1019 BRCA1/2 PVs carrier individuals affected with breast cancer and representative of the heterogeneous national population. Each individual was assigned to the Bergamo or non-Bergamo cohort based on self-reported birthplace. Our data indicate that the Bergamo BRCA1/2 PV spectrum shows less heterogeneity with fewer different variants and an average higher frequency compared to that of the rest of Italy. Consistently, four PVs explained about 60% of all carriers. The majority of the Bergamo PVs originated locally with only two PVs clearly imported. The Bergamo BRCA1/2 PV spectrum appears to be private. Hence, the Bergamo population would be ideal to study the disease risk associated with local PVs in breast cancer and other disease-causing genes. Finally, our data suggest that the Bergamo population is a genetic isolate and further analyses are warranted to prove this notion.

Newborn Screening for Severe Combined Immunodeficiency: 10-Year Experience at a Single Referral Center (2009-2018).

In 2008, newborn screening (NBS) for severe combined immunodeficiency (SCID) began as a pilot study in Wisconsin and has recently been added to every state's newborn screen panel. The incidence of SCID is estimated at 1 per 58,000 births which may suggest infrequent NBS SCID screen positive results in states with low annual birth rates. In this study, we report our center's experience with NBS positive SCID screen referrals over a 10-year period. A total of 68 full-term newborns were referred to our center for confirmatory testing. Of these referrals, 50% were false positives, 12% were SCID diagnoses, 20% syndromic T cell lymphopenia (TCL) disorders, and 18% non-SCID, non-syndromic TCL. Through collaboration with our newborn screening lab, second-tier targeted gene sequencing was performed for newborns with SCID screen positive results from communities with known founder pathogenic variants and provided rapid genetic confirmation of SCID and non-SCID TCL disorders. Despite extensive genetic testing, two of the eight (25%) identified newborns with SCID diagnoses lacked a definable genetic defect. Additionally, our referrals included ten newborns who were otherwise healthy newborns with idiopathic TCL and varied CD3+ T cell number longitudinal trajectories. Collectively, referrals to our single site over a 10-year period describe a broad spectrum of medically actionable and idiopathic TCL disorders which highlight the importance of clinical immunology expertise in all states, demonstrate efficiencies and challenges for second-tier genetic testing, and further emphasize the need to development standardized evaluation algorithms for non-SCID TCL.

Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study

BackgroundMorquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa.ResultsA total of 33 patients, aged 5–63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease.ConclusionsIn Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.

Screening of BRCA1 and BRCA2 germline mutations in unselected triple‐negative breast cancer patients: A series from north of Morocco

AbstractBackgroundTriple‐negative breast cancer (TNBC) is strongly associated with BRCA1 and BRCA2 germline pathogenic variants. Revised NCCN guidelines recommend that TNBC patients ≤60 years of age should be referred for genetic counseling and consideration of BRCA1/2 testing. The aim of the present study is to characterize germline BRCA1 and BRCA2 variants in a series of TNBC patients from the north of Morocco.MethodsWe analyzed BRCA1 and BRCA2 genes by next generation sequencing in a cohort of 32 patients unselected for family history and age of diagnosis.ResultsAmong 32 patients with TNBC, 7 carried a pathogenic BRCA1 or BRCA2 variant (21.87%). Six patients carried a pathogenic BRCA1 variant and one carried a pathogenic BRCA2 variant. Overall, six different pathogenic BRCA1 or BRCA2 variants were identified, including frameshift, nonsense, and missense variants. The BRCA1 missense c.5309G&gt;T, a founder pathogenic variant in the Moroccan population, was identified in two unrelated patients. In addition, six variants of unknown clinical significance were identified.ConclusionsThe understanding of BRCA1 and BRCA2 status in TNBC patients plays an important role in optimizing the preventive and therapeutic management. Despite the small size of our cohort, we believe that this work would help broaden our knowledge of TNBC and BRCA1/2 variants in Morocco.

Evidence for an ancient BRCA1 pathogenic variant in inherited breast cancer patients from Senegal

BRCA1 and BRCA2 are the most incriminated genes in inherited breast/ovarian cancers. Several pathogenic variants of these genes conferring genetic predisposition have been described in different populations but rarely in sub-Saharan Africa. The objectives of this study were to identify pathogenic variants of the BRCA genes involved in hereditary breast cancer in Senegal and to search for a founder effect. We recruited after free informed consent, 27 unrelated index cases diagnosed with breast cancer and each having a family history. Mutation screening of the genes identified a duplication of ten nucleotides c.815_824dupAGCCATGTGG, (p.Thr276Alafs) (NM_007294.3) located in exon 11 of BRCA1 gene, in 15 index cases (allelic frequency 27.7%). The pathogenic variant has been previously reported in African Americans as a founder mutation of West African origin. Haplotypes analysis of seven microsatellites surrounding the BRCA1 gene highlights a shared haplotype encompassing ~400 kb between D17S855 and D17S1325. This haplotype was not detected in none of 15 healthy controls. Estimation of the age of the pathogenic variant suggested that it occurred ~1400 years ago. Our study identified a founder pathogenic variant of BRCA1 predisposing to breast cancer and enabled the establishment of an affordable genetic test as a mean of prevention for Senegalese women at risk.

Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a heart disorder caused by autosomal dominant alterations affecting both sarcomeric genes and other nonsarcomeric loci in a minority of cases. However, in some patients, the occurrence of the causal pathogenic variant or variants in homozygosity, compound heterozygosity, or double heterozygosity has also been described. Most of the HCM pathogenic variants are missense and unique, but truncating mutations of the MYBPC3 gene have been reported as founder pathogenic variants in populations from Finland, France, Japan, Iceland, Italy, and the Netherlands. This study aimed to assess the genetic background of HCM in a cohort of Polish patients. Twenty‑nine Polish patients were analyzed by a next generation sequencing panel including 404 cardiovascular genes. Pathogenic variants were found in 41% of the patients, with ultra‑ rare MYBPC3 c.2541C>G (p.Tyr847Ter) mutation standing for a variant hotspot and correlating with a lower age at HCM diagnosis. Among the nonsarcomeric genes, the CSRP3 mutation was found in a single case carrying the novel c.364C>T (p.Arg122Ter) variant in homozygosity. With this finding, the total number of known HCM cases with human CSRP3 knockout cases has reached 3. This report expands the mutational spectrum and the inheritance pattern of HCM.

Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients.

The identification and interpretation of germline BRCA1/2 variants become increasingly important in breast and ovarian cancer (OC) treatment. However, there is no comprehensive analysis of the germline BRCA1/2 variants in a Chinese population. Here we performed a systematic review and meta-analysis on such variants from 94 publications. A total of 2,128 BRCA1/2 variant records were extracted, including 601 from BRCA1 and 632 from BRCA2. In addition, 414, 734, 449, and 307 variants were also recorded in the BIC, ClinVar, ENIGMA, and UMD databases, respectively, and 579 variants were newly reported. Subsequent analysis showed that the overall germline BRCA1/2 pathogenic variant frequency was 5.7% and 21.8% in Chinese breast and OC, respectively. Populations with high-risk factors exhibited a higher pathogenic variant percentage. Furthermore, the variant profile in Chinese is distinct from that in other ethnic groups with no distinct founder pathogenic variants. We also tested our in-house American College of Medical Genetics-guided pathogenicity interpretation procedure for Chinese BRCA1/2 variants. Our results achieved a consistency of 91.2-97.6% (5-grade classification) or 98.4-100% (2-grade classification) with public databases. In conclusion, this study represents the first comprehensive meta-analysis of Chinese BRCA1/2 variants and validates our in-house pathogenicity interpretation procedure, thereby providing guidance for further PARP inhibitor development and companion diagnostics in the Chinese population.