Genetic Counseling Challenges Research Articles

Clinical relevance of double heterozygosity revealed by next-generation sequencing of homologous recombination repair pathway genes in South African breast cancer patients

PurposeGenetically predisposed breast cancer (BC) patients represent a minor but clinically meaningful subgroup of the disease, with 25% of all cases associated with actionable variants in BRCA1/2. Diagnostic implementation of next-generation sequencing (NGS) resulted in the rare identification of BC patients with double heterozygosity for deleterious variants in genes partaking in homologous recombination repair of DNA. As clinical heterogeneity poses challenges for genetic counseling, this study focused on the occurrence and clinical relevance of double heterozygous BC in South Africa.MethodsDNA samples were diagnostically screened using the NGS-based Oncomine™ BRCA Expanded Research Assay. Data was generated on the Ion GeneStudio S5 system and analyzed using the Torrent Suite™ and reporter software. The clinical significance of the variants detected was determined using international variant classification guidelines and treatment implications.ResultsSix of 1600 BC patients (0.375%) tested were identified as being bi-allelic for two germline likely pathogenic or pathogenic variants. Most of the variants were present in BRCA1/2, including two founder-related small deletions in three cases, with family-specific variants detected in ATM, BARD1, FANCD2, NBN, and TP53. The scientific interpretation and clinical relevance were based on the clinical and tumor characteristics of each case.ConclusionThis study increased current knowledge of the risk implications associated with the co-occurrence of more than one pathogenic variant in the BC susceptibility genes, confirmed to be a rare condition in South Africa. Further molecular pathology-based studies are warranted to determine whether clinical decision-making is affected by the detection of a second pathogenic variant in BRCA1/2 and TP53 carriers.

Women's preferences for NIPT as a first-line test in England and France: Challenges for genetic counseling practices.

Non-invasive prenatal testing (NIPT) is provided in the private and public sectors worldwide as a first- or second-tier test. In England and France, NIPT is fully funded and offered as a contingent strategy with different probability cut-offs (1:150 and 1:1000). These different approaches to define the target population for NIPT have implications for how women experience their antenatal care. The paper explores and compares the perceptions and difficulties of women in England and France who took NIPT as a second-tier screening test. It is based on a semi-structured qualitative interview study with 17 women in England and France conducted between September 2021 and May 2022. The interviews were cross-analyzed using thematic analysis. Our findings show that most women express a preference for the offer of NIPT as a first-line screening test. Some issues with the contingent model, related to the access to information and termination of pregnancy (TOP), the disparities of NIPT uptake, and risks of generating anxiety with combined first-trimester screening (cFTS), could be addressed by a universal strategy for T21, T13, and T18. Nevertheless, this strategy could present some challenges for genetic counseling due to: women's understanding and expectations of NIPT; adequate information and counseling about the scope and limits of NIPT; concerns about the routinization of NIPT in the first-line offer; limitations and uncertainties associated with the provision of expanded NIPT in France; the remaining importance of other screening tests; and associated costs.

Genetic Counseling Challenges: A Case Report of a 6-Year-Old Child with Developmental Delay and B-Acute Lymphoblastic Leukemia

Background: A 34-year-old father attended the Genetic Counseling session with concerns of the previous child who had a developmental delay (DD) and developed B-cell acute lymphoblastic leukemia at 4 years of age. Genetic evaluation for DD was suggested at 2 years and was not done. At the age of 4 years, she developed acute lymphoblastic leukemia and died due to a relapse at 6 years of age. He was concerned about his offspring’s risk for the above disorders. Investigations: First-tier genetic workup of chromosomal analysis revealed an abnormal mosaic karyotype of addition of chromosome 9p22, ?11p and monosomy 21 and florescence in situ hybridization revealed gain in 21q22 in most of the cells. Clinical exome sequencing showed a 17.25 Mb deletion in chromosome 8 and variant of unknown significance in the NUP214 gene. Chromosomal microarray detected a loss of 27.1 Mb in chromosome 8, gain of 102.3 Mb in chromosome 8p11.22q24.3 and 1.1 Mb chromosome 14q31.1q32.2. Conclusion: This case report will highlight the importance of early genetic testing and challenges in genetic counseling in view of hematological malignancy in a child with preexisting DD.

Frequency and spectrum of CHEK2 variants in a large Brazilian set of germline-tested patients.

e22539 Background: CHEK2 is one of the most commonly affected genes in different cancers. P/LP variants can display differences in phenotype and in penetrance in cancer families. Some of the most frequently described variants largely vary from population to population. CHEK2 variants are distributed in the whole gene sequence and it seems that some functional areas can be critical. Additionally, a significant number of variants detected in CHEK2 are classified as VUS and require appropriate functional testing for accurate classification. Therefore, we decided to contribute with databases presenting the largest cohort of CHEK2 P/LP and VUS detected through NGS panels in many cancer centers throughout Brazil. Methods: We conducted a retrospective cohort study including CHEK2 variant carriers identified by genetic testing ordered by Grupo Oncoclinicas health care professionals from 2017 to 2022. Primary endpoint was to describe the prevalence of CHEK2 P/LP and VUS and variants categories as well as sex at birth, age at diagnosis, phenotype and geographic distribution. Results: A total of 207 carriers of CHEK2 variants were identified, with 96 (46%) classified as P/LP and 111 (54%) as VUS. Majority of patients were female (88%), with median age at diagnosis of 45 years for those with P/LP variants. The most observed phenotype was breast cancer (125 cases, 60%), followed by prostate (11.5%), ovarian (7%), thyroid (2%) and kidney cancer (1%). Approximately 25% of patients either had a less common type of cancer, lacked a reported cancer diagnosis, or did not provide information regarding the specific type of cancer. The most frequent variants were p.Arg117Gly (14.5%) and p.Ile157Thr (7.2%). Despite being predominantly described in association with breast cancer in North American, c.1100del variant was the third most frequent in our population, occurring in 14 (6.7%) cases, with breast cancer being its slightly more common phenotype 57.1% (8/14 patients). Among p.Arg117Gly carriers, breast cancer was also the most frequently observed phenotype, accounting for 23 out of 30 patients (76.7%), whereas among p.Ile157Thr carriers, it represented a lower proportion of cases, 5 out of 15 patients (33.3%). Of the 207 patients, 58.4% were from the Southeast region and 25% were from the South region. Conclusions: This study is the largest cohort of germinative CHEK2 variants reported in Brazil, which showed p.Arg117Gly and p.Ile157Thr to be the most prevalent variants and breast cancer to be the most common phenotype, particularly among carriers of the p.Arg117Gly variant. The significant number of VUS identified, however, represents a challenge for genetic counseling in developing countries and highlights the need for further research to classify these variants as well as for functional testing to improve understanding about their association with cancer.

Hereditary Breast Cancer in Romania-Molecular Particularities and Genetic Counseling Challenges in an Eastern European Country.

In Romania, breast cancer (BC) is the most common malignancy in women. However, there is limited data on the prevalence of predisposing germline mutations in the population in the era of precision medicine, where molecular testing has become an indispensable tool in cancer diagnosis, prognosis, and therapeutics. Therefore, we conducted a retrospective study to determine the prevalence, mutational spectrum, and histopathological prediction factors for hereditary breast cancer (HBC) in Romania. A cohort of 411 women diagnosed with BC selected upon NCCN v.1.2020 guidelines underwent an 84-gene NGS-based panel testing for breast cancer risk assessment during 2018-2022 in the Department of Oncogenetics of the Oncological Institute of Cluj-Napoca, Romania. A total of 135 (33%) patients presented pathogenic mutations in 19 genes. The prevalence of genetic variants was determined, and demographic and clinicopathological characteristics were analyzed. We observed differences among BRCA and non-BRCA carriers regarding family history of cancer, age of onset, and histopathological subtypes. Triple-negative (TN) tumors were more often BRCA1 positive, unlike BRCA2 positive tumors, which were more often the Luminal B subtype. The most frequent non-BRCA mutations were found in CHEK2, ATM, and PALB2, and several recurrent variants were identified for each gene. Unlike other European countries, germline testing for HBC is still limited due to the high costs and is not covered by the National Health System (NSH), thus leading to significant discrepancies related to the screening and prophylaxis of cancer.

Variable Clinical Presentation in Individuals with Truncating Variants in DDX41

Background and AimsDefects in DDX41 have previously been associated with increased risk of myeloid neoplasms, lymphoid neoplasms, cytopenia, and red blood cell macrocytosis. DDX41-related phenotypes have a variable age of onset typically in the 60 s. A previous study analyzed a cohort of 1,385 individuals with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), identifying 33 individuals with a pathogenic variant in DDX41, 9 of whom had a familial history of MDS/AML. In our cohort of 6,103 participants with diverse clinical manifestations, we identified 7 individuals with truncating variants in DDX41. We sought to characterize age-related penetrance and the phenotypic spectrum of individuals with DDX41 truncating variants. MethodsWe performed exome or genome sequencing on DNA extracted from blood, saliva, fibroblasts, or EBV-transformed cell lines in individuals referred to the Centralized Sequencing Program at the NIH for immune-related, neurological, psychiatric, and other clinical indications. ResultsWe identified 7 subjects with truncating variants in DDX41, including 3 different frameshift variants in 5 subjects and 2 different nonsense variants in the other 2 subjects. The average age of subjects was 37 years old, ranging from 5 to 76 years old at time of enrollment. There were 3 males and 4 females. Family history of DDX41-related phenotypes was not reported in the families; furthermore, there were no familial cases, thought segregation data was incomplete. Clinical features were highly variable, ranging from a healthy volunteer to an individual with JAK2 p. Val617Phe-associated eosinophilic myeloid neoplasm. Previously associated DDX41-related phenotypes were not observed in the 7 subjects even include those above 60. ConclusionsHere, we report 7 subjects with truncating variants in DDX41. These individuals have variable immune phenotypes and further studies are necessary to delineate whether they are attributed to DDX41 truncating variants. Detection of DDX41-defects in younger individuals prior to symptom onset poses genetic counseling challenges given the long latency period and minimal evidence-based management guidelines at present. Nonetheless, current expert-based clinical recommendations for management and monitoring may provide clinical benefit upon further study. Additional studies of clinical and sub-clinical features in expanded cohorts are warranted to further delineate DDX41-related disease risk.

Trends in the Prevalence of Births with Chromosomal Abnormalities - Haidian District, Beijing Municipality, China, 2013-2022.

The primary causes of early miscarriage and stillbirth are chromosomal abnormalities (CAs) whose prevalence has been observed to increase in recent years. According to data received from a hospital-based birth-defect surveillance system in the Haidian District, Beijing, there was a significant increase in the prevalence of CAs along with most subtypes from 2013 to 2022. This noted increase in the reported prevalence is potentially attributable to factors such as a rise in maternal age, alongside the enhanced detection efficacy resulting from the utilization of noninvasive prenatal testing. The escalating prevalence of sex CAs and other previously rare CAs pose novel challenges for genetic counseling and healthcare practitioners. These professionals are tasked with the accurate evaluation and interpretation of detection data, which must then be conveyed appropriately to patients. Furthermore, it is imperative to intensify health education efforts to assist women in making informed treatment decisions, considering the diverse prognoses associated with different CAs.

BHLHA9 homozygous duplication in a consanguineous family: A challenge for genetic counseling.

Split-hand/foot malformation (SHFM) with long-bone deficiency (SHFLD) is a rare condition characterized by SHFM associated with long-bone malformation usually involving the tibia. It includes three different types; SHFLD1 (MIM % 119,100), SHFLD2 (MIM % 610,685) and SHFLD3 (MIM # 612576). The latter was shown to be the most commonly reported with a duplication in the 17p13.1p13.3 locus that was narrowed down to the BHLHA9 gene. Here, we report a consanguineous Lebanese family with three members presenting with limb abnormalities including tibial hemimelia. One of these patients presented with additional bowing fibula and another with bilateral split hand. CGH array analysis followed by RQ-PCR allowed us to detect the first homozygous duplication on the short arm of chromosome 17p13.3 including the BHLHA9 gene and involved in SHFLD3. Interestingly, one patient with the homozygous duplicated region, carrying thus four BHLHA9 copies presented with long bone deficiency but no SHFM. The incomplete penetrance and the variable expressivity of the disease in this family as well as the presence of the BHLHA9 homozygous duplication rendered genetic counseling extremely challenging and preimplantation genetic diagnosis almost impossible.

CN18 Challenges in genetic counseling in hereditary cancer syndromes in Mexican population and prevention clinic experience

In Mexico genetic counseling is given by medical geneticists, the access is scarce added to socioeconomic characteristics of the population, reaching a definitive diagnosis in hereditary cancer syndromes is difficult. Therefore is underdiagnosed. The CUCC (Centro Universitario Contra el Cáncer) Early Cancer Detection Clinic (CECIL) create a model in which open population could enroll in a prevention cancer screening program.

Arrhythmias as Presentation of Genetic Cardiomyopathy.

There is increasing evidence regarding the prevalence of genetic cardiomyopathies, for which arrhythmias may be the first presentation. Ventricular and atrial arrhythmias presenting in the absence of known myocardial disease are often labelled as idiopathic, or lone. While ventricular arrhythmias are well-recognized as presentation for arrhythmogenic cardiomyopathy in the right ventricle, the scope of arrhythmogenic cardiomyopathy has broadened to include those with dominant left ventricular involvement, usually with a phenotype of dilated cardiomyopathy. In addition, careful evaluation for genetic cardiomyopathy is also warranted for patients presenting with frequent premature ventricular contractions, conduction system disease, and early onset atrial fibrillation, in which most detected genes are in the cardiomyopathy panels. Sudden death can occur early in the course of these genetic cardiomyopathies, for which risk is not adequately tracked by left ventricular ejection fraction. Only a few of the cardiomyopathy genotypes implicated in early sudden death are recognized in current indications for implantable cardioverter defibrillators which otherwise rely upon a left ventricular ejection fraction ≤0.35 in dilated cardiomyopathy. The genetic diagnoses impact other aspects of clinical management such as exercise prescription and pharmacological therapy of arrhythmias, and new therapies are coming into clinical investigation for specific genetic cardiomyopathies. The expansion of available genetic information and implications raises new challenges for genetic counseling, particularly with the family member who has no evidence of a cardiomyopathy phenotype and may face a potentially negative impact of a genetic diagnosis. Discussions of risk for both probands and relatives need to be tailored to their numeric literacy during shared decision-making. For patients presenting with arrhythmias or cardiomyopathy, extension of genetic testing and its implications will enable cascade screening, intervention to change the trajectory for specific genotype-phenotype profiles, and enable further development and evaluation of emerging targeted therapies.

Reclassification of Five BRCA1/2 Variants with Unknown Significance Using Complex Functional Study

PurposeWhile BRCA1/2 genes are commonly investigated, variants of unknown significance (VUS) and variants with potential splice effect are still being detected and they represent a substantial challenge in genetic counseling and therapy.Materials and MethodsOut of genetically tested 3,568 hereditary breast and ovarian cancer probands five, functionally not investigated variants with potential splice-modifying effect were subjected to functional characterization. Transcript-level analysis on peripheral blood-derived RNA of the carriers was performed to test aberrant splicing. The completeness of the aberrant splicing event was also studied, existence and extent of nonsense-mediated decay was even addressed. Clinical and phenotype data, pedigree and co-segregation analyses were also done. Locus-specific loss of heterozygosity (LOH) in tumor tissues was additionally tested.ResultsIn case of the BRCA1:c.4484+4dupA and the BRCA1:c.5407-10G>A variants functional results allowed us to reclassify them from VUS into likely pathogenic category. BRCA1:c.4358-31A>C, by producing incomplete aberrant splicing, was highlighted as strong VUS, but in lack of other supporting evidence, re-categorization was not possible. The likely pathogenic assertion of previously not reported BRCA2:c.8487G>T was reinforced based on its spliceogenic property and tumor LOH, while BRCA2:c.793G>A failed to present aberrant splicing in spite of suggestive predictions, which altered its original VUS evaluation into likely benign class.ConclusionWe presented molecular and clinical evidence for reclassification of four out of five BRCA1/2 variants. Both up- and down-classification harbour important clinical significance. Patients carrying re-classified pathogenic variants in the future will not be dropped out from medical surveillance, preventive measures, treatment and predictive family screening in relatives at risk.

Challenges in genetic counseling for congenital anomalies of the kidneys and urinary tract (CAKUT) spectrum

Abstract Objectives Congenital anomalies of the kidneys and urinary tract (CAKUT) are one of the most common sets of congenital defects. Bilateral renal agenesis is a severe presentation of the CAKUT spectrum. Case presentation We report on two families who presented with recurrent pregnancies affected with bilateral renal agenesis and negative family histories. Likely pathogenic variants in the GREB1L gene were identified in the affected pregnancies and subsequently in their asymptomatic fathers. The first familial variant was identified by a multi-gene CAKUT panel and the second by whole exome sequencing. Renal ultrasound showed the father in family 1 had asymptomatic unilateral pelvic kidney and the father in family 2 had no apparent renal anomalies. Conclusions Recent identification of genes responsible for CAKUT allows for genetic testing of affected families. Identification of the genetic etiology of CAKUT cases has multiple benefits including accurate risk assessment and reproductive options. Genetic counseling around CAKUT is challenging due to the extreme variability in presentation of the disorders.

Genetic counseling and testing for hereditary hemorrhagic telangiectasia.

Genetic counseling is an important means of identifying a patient's genetic risk of hereditary hemorrhagic telangiectasia (HHT) and assisting patients in making informed decisions about their health. With an increase in understanding of the genetic mechanisms underlying HHT over the last decade, genetic counseling is increasingly being incorporated into the care of patients affected by HHT. In addition to refining the diagnosis of symptomatic patients, genetic testing can help to distinguish asymptomatic, at-risk patients from those who are unaffected by HHT. The purpose of this review article is to summarize the current knowledge regarding the role of genetic counseling and genetic testing in identifying and managing HHT in at-risk populations. This article also reviews the guidelines, outcomes, risks, and challenges of genetic counseling and testing for HHT in various patient populations, and provides an algorithm for the use of genetic counseling in symptomatic and asymptomatic patients.

Challenges in genetic counseling for hereditary endocrine neoplasia syndromes

Challenges in genetic counseling for hereditary endocrine neoplasia syndromes

Next‐generation sequence‐based preimplantation genetic testing for monogenic disease resulting from maternal mosaicism

ABSTRACTBackgroundMosaicism poses challenges for genetic counseling and preimplantation genetic testing for monogenic disorders (PGT‐M). NGS‐based PGT‐M has been extensively used to prevent the transmission of monogenic defects, but it has not been evaluated in the application of PGT‐M resulting from mosaicism.MethodsFour women suspected of mosaicism were confirmed by ultra‐deep sequencing. Blastocyst trophectoderm cells and polar bodies were collected for whole genome amplification, followed by pathogenic variants detection and haplotype analysis based on NGS. The embryos free of the monogenic disorders were transplantable.ResultsUltra‐deep sequencing confirmed that the four women harbored somatic mosaic variants, with the proportion of variant cells at 1.12%, 9.0%, 27.60%, and 91.03%, respectively. A total of 25 blastocysts were biopsied and detected during four PGT cycles and 5 polar bodies were involved in one cycle additionally. For each couple, a wild‐type embryo was successfully transplanted and confirmed by prenatal diagnosis, resulting in the birth of four healthy infants.ConclusionsMosaic variants could be effectively evaluated via ultra‐deep sequencing, and could be prevented the transmission by PGT. Our work suggested that an NGS‐based PGT approach, involving pathogenic variants detection combined with haplotype analysis, is crucial for accurate PGT‐M with mosaicism.

Actionable secondary findings in arrhythmogenic right ventricle cardiomyopathy genes: impact and challenge of genetic counseling.

Comprehensive genetic analysis yields in a higher diagnostic rate but also in a higher number of secondary findings (SF). American College of Medical Genetics and Genomics (ACMG) published a list of 59 actionable genes for which disease causing sequence variants are recommended to be reported as SF including 27 genes linked to inherited cardiovascular disease (CVD) such as arrhythmia syndromes, cardiomyopathies and vascular and connective tissue disorders. One of the selected conditions represented in the actionable gene list is the arrhythmogenic right ventricle cardiomyopathy (ARVC), an inherited heart muscle disease with a particularly high risk of sudden cardiac death (SCD). Since clinical symptoms are frequently absent before SCD, a genetic finding is a promising option for early diagnosis and possible intervention. However, the variant interpretation and the decision to return a SF is still challenging. To determine the frequency of medically actionable SF linked to CVD we analyzed data of 6,605 individuals who underwent high throughput sequencing for noncardiac diagnostic requests. In particular, we critically assessed and classified the variants in the ARVC genes: DSC2, DSG2, DSP, PKP2 and TMEM43 and compared our findings with the population-based genome Aggregation Database (gnomAD) and ARVC-afflicted individuals listed in ClinVar and ARVC database. 1% (69/6,605) of tested individuals carried pathogenic SF in one of the 27 genes linked to CVD, of them 13 individuals (0.2%) carried a pathogenic SF in a ARVC gene. Overall, 582 rare variants were identified in all five ARVC genes, 96% of the variants were missense variants and 4% putative LoF variants (pLoF): frameshift, start/stop-gain/loss, splice-site. Finally, we selected 13 of the 24 pLoF variants as pathogenic SF by careful data interpretation. Since SF in actionable ARVC genes can allow early detection and prevention of disease and SCD, detected variant must undergo rigorous clinical and laboratory evaluation before it can be described as pathogenic and returned to patients. Returning a SF to a patient should be interdisciplinary, it needs genetic counselling and clinicians experienced in inherited heart disease.

Preimplantation Genetic Testing for Monogenic Disorders.

Preimplantation genetic testing (PGT) has evolved into a well-established alternative to invasive prenatal diagnosis, even though genetic testing of single or few cells is quite challenging. PGT-M is in theory available for any monogenic disorder for which the disease-causing locus has been unequivocally identified. In practice, the list of indications for which PGT is allowed may vary substantially from country to country, depending on PGT regulation. Technically, the switch from multiplex PCR to robust generic workflows with whole genome amplification followed by SNP array or NGS represents a major improvement of the last decade: the waiting time for the couples has been substantially reduced since the customized preclinical workup can be omitted and the workload for the laboratories has decreased. Another evolution is that the generic methods now allow for concurrent analysis of PGT-M and PGT-A. As innovative algorithms are being developed and the cost of sequencing continues to decline, the field of PGT moves forward to a sequencing-based, all-in-one solution for PGT-M, PGT-SR, and PGT-A. This will generate a vast amount of complex genetic data entailing new challenges for genetic counseling. In this review, we summarize the state-of-the-art for PGT-M and reflect on its future.

Prenatal diagnosis of a maternal 7.22-Mb deletion at chromosome 4q32.2q32.3 by SNP array

BackgroundAlthough Chromosomal microarray analysis (CMA) is a powerful diagnostic technology for detecting chromosomal copy number variants (CNVs), it detects numerous variants of unknown significance (VUSs), which poses a great challenge for genetic counselling. Terminal deletion of the long arm of chromosome 4 is a rare genetic aberration. Few cases of interstitial deletion sharing the common deleted segment have been reported.Case presentationA male foetus with a 7.22-Mb deletion at chromosome 4q32.2q32.3 was found in the proband. The paternal genotype was normal. His asymptomatic mother with a normal phenotype and intelligence was found to carry the same deletion at the long arm of chromosome 4. The clinical significance of arr[GRCh37] 4q32.2q32.3(162858958_170081268)×1 remains uncertain. To the best of our knowledge, this is the first case report on a VUS of 4q32 deletion and the second report of a heterochromatic CNV involving part of the long arm of chromosome 4 in a phenotypically normal mother and child. The identification of this case contributes to additional understanding of deletion at 4q32.2q32.3. This report may provide a reference for prenatal diagnosis and genetic counselling in patients who have genotypes of similar cytogenetic abnormalities.ConclusionsThe novel 7.22-Mb deletion at chromosome 4q32.2q32.3 (162858958-170081268) is a VUS. The foetus inherited this VUS from a phenotypically normal mother.

Genetic mosaicism in haemophilia: A practical review to help evaluate the risk of transmitting the disease.

Approximately 70% of patients with haemophilia exhibit a clear inheritance pattern, while for the remaining 30%, patients are the first to be diagnosed in their family and are considered sporadic cases. In such a setting, the determination of carrier status and the risk estimation of disease transmission to another child are major challenges for genetic counselling. Large studies have suggested that genetic testing reveals 70% of sporadic patients' mothers are carriers. In the remaining 30%, in some apparently non-carrier mothers, the pathogenic variant can be detected as low somatic and gonosomal mosaicism. The significance of mosaic pathogenic variants has thus far been underestimated, since conventional Sanger sequencing and other technology are not sufficiently sensitive. The study of various tissue samples and recent extra-sensitive molecular methods have now made it easier to detect both single-nucleotide variants (SNVs) and copy-number variants (CNVs), at a mosaic level in parents, and to predict the probability of disease recurrence. This review seeks to examine various kinds of mosaicism in haemophilia, including the mechanisms by which they arise and the risk of passing these variants on to the next generation. In addition, we focus on the selection of cell tissues and methods to detect these mosaic variants in the haemophilia setting. Taking into account the high rate of mosaicism in mothers of sporadic cases, we propose a diagnostic flow chart that could facilitate better evaluation of the risk of transmitting haemophilia in genetic and prenatal counselling.

CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer.

Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.