Clinical Genetic Counseling Research Articles

Assessing sensitivity to change of the genomics outcome scale (GOS).

The Genetic Counseling Outcome Scale (GCOS-24) is a 24-item patient-reported outcome measure (PROM) that was developed to evaluate genetic counseling and testing services by measuring the construct of empowerment. The Genomics Outcome Scale (GOS) is a 6-item version of GCOS-24 that was designed to provide a PROM for use both within and outside clinical genetics services and reduce respondent burden. However, unlike GCOS-24, the sensitivity to change of the GOS has not yet been assessed in appropriate clinical settings. We carried out pre- and post-clinic surveys using the GOS to assess sensitivity to change of the GOS and produce before-and-after GOS data as part of a service evaluation. The survey was sent to patients attending the genetic counseling clinic for a first appointment at the All Wales Medical Genetic Service from 8 April 2019 to 18 September 2019. Patients attending disease management clinics, where genetic issues were not the primary concern, were excluded from this study. A total of 138 respondents were included in the final analysis. The result shows that empowerment scores, measured using the GOS, were significantly higher (p<0.05) after clinic attendance. The GOS shows good sensitivity to change, with a medium-to-large effect size (Cohen's d=0.73). The result also shows that the service is delivering measurable benefits for its service users.

Childhood and Early Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry

To report the relative frequencies of childhood and early onset glaucoma subtypes and their genetic findings in a large single cohort. Retrospective clinical and molecular study. All individuals with childhood glaucoma (diagnosed 0 to <18 years) and early onset glaucoma (diagnosed 18 to <40 years) referred to a national disease registry. We retrospectively reviewed the referrals of all individuals with glaucoma diagnosed at <40 years of age recruited to the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Subtypes of glaucoma were determined using the Childhood Glaucoma Research Network (CGRN) classification system. DNA extracted from blood or saliva samples underwent sequencing of genes associated with glaucoma. The phenotype and genotype distribution of glaucoma diagnosed at <40 years of age. A total of 290 individuals (533 eyes) with childhood glaucoma and 370 individuals (686 eyes) with early onset glaucoma were referred to the ANZRAG. Primary glaucoma was the most prevalent condition in both cohorts. In the childhood cohort, 57.6% of individuals (167/290, 303 eyes) had primary congenital glaucoma (PCG), and 19.3% (56/290, 109 eyes) had juvenile open-angle glaucoma. Juvenile open-angle glaucoma constituted 73.2% of the early onset glaucoma cohort (271/370, 513 eyes). Genetic testing in probands resulted in a diagnostic yield of 24.7% (125/506) and a reclassification of glaucoma subtype in 10.4% of probands (13/125). The highest molecular diagnostic rate was achieved in probands with glaucoma associated with nonacquired ocular anomalies (56.5%). Biallelic variants in CYP1B1 (n= 29, 23.2%) and heterozygous variants in MYOC (n= 24, 19.2%) and FOXC1 (n= 21, 16.8%) were most commonly reported among probands with a molecular diagnosis. Biallelic CYP1B1 variants were reported in twice as many female individuals as male individuals with PCG (66.7% vs. 33.3%, P= 0.02). We report on the largest cohort of individuals with childhood and early onset glaucoma from Australasia using the CGRN classification. Primary glaucoma was most prevalent. Genetic diagnoses ascertained in 24.7% of probands supported clinical diagnoses and genetic counseling. International collaborative efforts are required to identify further genes because the majority of individuals still lack a clear molecular diagnosis.

OP509 - Clinical genetic counselor experience in the new/expanded adoption of telehealth in the US and Canada during the COVID-19 pandemic

OP509 - Clinical genetic counselor experience in the new/expanded adoption of telehealth in the US and Canada during the COVID-19 pandemic

Analysis of ASXL3 gene variant in a child with Bainbridge-Ropers syndrome

To explore the genetic basis for a child affected with Bainbridge-Ropers syndrome. Genomic DNA was extracted from peripheral venous blood samples from the patient and his parents. Whole exome sequencing (WES) was carried out to detect genetic variant of the proband. Candidate variant was verified by Sanger sequencing. The 3-year-old boy presented with psychomotor retardation, linguistic difficulties, mental retardation and peculiar craniofacial phenotype. A de novo heterozygous nonsense variant of the ASXL3 gene, c.3106C>T, was identified by WES in the proband, and the same mutation was not found among his parents. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.3106C>T variant was predicted to be pathogenic (PVS1+PS2+PP4). The heterozygous variant c.3106C>T of the ASXL3 gene probably underlies the Bainbridge-Ropers syndrome in the patient. Above result has enabled the clinical diagnosis and genetic counseling for the family.

Genetic counseling and testing practices for late-onset neurodegenerative disease: a systematic review.

ObjectiveTo understand contemporary genetic counseling and testing practices for late-onset neurodegenerative diseases (LONDs), and identify whether practices address the internationally accepted goals of genetic counseling: interpretation, counseling, education, and support.MethodsFour databases were systematically searched for articles published from 2009 to 2020. Peer-reviewed research articles in English that reported research and clinical genetic counseling and testing practices for LONDs were included. A narrative synthesis was conducted to describe different practices and map genetic counseling activities to the goals. Risk of bias was assessed using the Qualsyst tool. The protocol was registered with PROSPERO (CRD42019121421).ResultsSixty-one studies from 68 papers were included. Most papers focused on predictive testing (58/68) and Huntington’s disease (41/68). There was variation between papers in study design, study population, outcomes, interventions, and settings. Although there were commonalities, novel and inconsistent genetic counseling practices were identified. Eighteen papers addressed all four goals of genetic counseling.ConclusionContemporary genetic counseling and testing practices for LONDs are varied and informed by regional differences and the presence of different health providers. A flexible, multidisciplinary, client- and family-centered care continues to emerge. As genetic testing becomes a routine part of care for patients (and their relatives), health providers must balance their limited time and resources with ensuring clients are safely and effectively counseled, and all four genetic counseling goals are addressed. Areas of further research include diagnostic and reproductive genetic counseling/testing practices, evaluations of novel approaches to care, and the role and use of different health providers in practice.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-021-10461-5.

Disclosure of clinically actionable genetic variants to thoracic aortic dissection biobank participants

BackgroundDisclosure of pathogenic variants to thoracic aortic dissection biobank participants was implemented. The impact and costs, including confirmatory genetic testing in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, were evaluated.MethodsWe exome sequenced 240 cases with thoracic aortic dissection and 258 controls, then examined 11 aortopathy genes. Pathogenic variants in 6 aortopathy genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 participants, representing 10.8% of the cohort (26/240). A second research sample was used to validate the initial findings. Mailed letters to participants disclosed that a potentially disease causing DNA alteration had been identified (neither the gene nor variant was disclosed). Participants were offered clinical genetic counseling and confirmatory genetic testing in a CLIA laboratory.ResultsExcluding 6 participants who were deceased or lost to follow-up, 20 participants received the disclosure letter, 10 of whom proceeded with genetic counseling, confirmatory genetic testing, and enrolled in a survey study. Participants reported satisfaction with the letter (4.2 ± 0.7) and genetic counseling (4.4 ± 0.4; [out of 5, respectively]). The psychosocial impact was characterized by low decisional regret (11.5 ± 11.6) and distress (16.0 ± 4.2, [out of 100, respectively]). The average cost for 26 participants was $400, including validation and sending letters. The average cost for those who received genetic counseling and CLIA laboratory confirmation was $605.ConclusionsParticipants were satisfied with the return of clinically significant biobank genetic results and CLIA laboratory testing; however, the process required significant time and resources. These findings illustrate the trade-offs involved for researchers considering returning research genetic results.

Analysis of the androgen receptor (AR) gene in a cohort of Indonesian undermasculinized 46, XY DSD patients

BackgroundPathogenic variants in the androgen receptor (AR) gene located on chromosome Xq11-12, are known to cause varying degrees of undermasculinization in 46, XY individuals. The aim of this study was to investigate the frequency of pathogenic variants in the AR gene in a cohort of 46, XY undermasculinized individuals from Indonesia who were suspected of having androgen insensitivity syndrome (AIS). All patients with 46, XY DSD referred to our center between 1994 and 2019 were collected from our clinical database. All 46, XY DSD patients without a prior molecular diagnosis with an external masculinization score (EMS) ≤ 9 were included in this study. All exons and intron–exon boundaries of AR gene were analyzed using Sanger sequencing to identify pathogenic variants of the AR gene.ResultsA cohort of 75 undermasculinized patients were selected for the study. Direct Sanger sequencing of all eight exons of the AR gene led to a genetic diagnosis in 11 patients (14.67%). All of the variants identified (p.Arg841His; p.Ile604Asn; p.Val731Met; p.Pro672Ser; p.Gln739Arg; p.Ser302Glufs*3) have been previously reported in patients with AIS.ConclusionsThis is the first study in Indonesia that highlights the significance of molecular analysis in providing a definitive diagnosis of AIS for patients with 46, XY DSD undermasculinization. This is an uncommon finding in the Indonesian population presenting with 46, XY DSD undermasculinization. A genetic diagnosis allows optimal clinical management and genetic counseling for patients and their families. As 46, XY DSD can be caused by pathogenic variants in other genes involved in gonadal development and differentiation, further genetic analysis, such as whole exome sequencing, should be carried out on those patients that did not carry an AR variant.

Clinical characteristics and genetic analysis of a Chinese pedigree affected with thiamine pyrophosphokinase deficiency

To investigate the clinical characteristics and genetic variant in a Chinese pedigree affected with thiamine pyrophosphokinase deficiency (TPKD). Clinical data of the pedigree were analyzed retrospectively and summarized from the perspectives of clinical manifestation, magnetic resonance imaging (MRI), and genotype. Relevant literature was also reviewed. The proband, a female, has developed paroxysmal ataxia with dystonia at the age of 2-year-and-8-month. The ataxia has recurred for 7-8 times. The child had died at 11 years old due to recurrence and aggravation of the disease. MRI showed diffuse symmetrical lesions of brain parenchyma and spinal cord. Her brother had similar symptoms and died at 6. The parents were consanguineous but healthy. Genetic testing revealed that the girl has carried homozygous c.161C>T variants of the TPK1 gene, suggesting the diagnosis of TPKD. So far 15 cases of TPKD have been reported, among which 9 were from consanguineous marriages. The disease usually occurs before the age of 3, and most patients had featured paroxysmal encephalopathy and recurrent infections. Symmetrical celebral cortex, basal ganglia and cerebellum lesions were common. Missense mutations of the TPK1 gene were common. Vitamin B1 was effective in some cases. For infants featuring encephalopathy, ataxia, dystonia and other phenotypes, early genetic testing should be recommended in order to provide guidance for clinical treatment and genetic counseling.

Noninvasive prenatal detection of fetal sex chromosome abnormalities using the semiconductor sequencing platform (SSP) in Southern China

BackgroundNoninvasive prenatal testing (NIPT) has been widely used to screen for fetal aneuploidies, including fetal sex chromosome aneuploidies (SCAs). However, there is less information on the performance of NIPT in detecting SCAs.MethodsA cohort of 47,800 pregnancies was recruited to review the high-risk NIPT results for SCAs. Cell-free fetal DNA (cffDNA) was extracted and sequenced. All NIPT high-risk cases were recommended to undergo invasive prenatal diagnosis for karyotyping analysis and chromosome microarray analysis (CMA).ResultsA total of 238 high-risk cases were detected by NIPT, including 137 cases of 45,X, 27 cases of 47,XXX, and 74 cases of 47,XYY/47,XXY. Prenatal diagnosis, including karyotyping analysis and CMA, was available in 170 cases. The positive predictive value (PPV) was 30.00% for 45,X, 70.58% for 47,XXX, and 81.13% for 47,XYY/47,XXY. In addition, 13 cases of sex chromosome mosaicism and 9 cases of sex chromosome CNVs were incidentally found in this study.ConclusionOur study showed that NIPT was reliable for screening SCAs based on a large sample, and it performed better in predicting sex chromosome trisomies than monosomy X. Our study will provide an important reference for clinical genetic counseling and further processing of the results.

One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver\u2013Russell syndrome

BackgroundSilver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented.Main bodyWe analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS.ConclusionsWES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.

Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss

BackgroundPrevious studies have revealed that mutations of Spalt Like Transcription Factor 1 (SALL1) are responsible for Townes-Brocks syndrome (TBS), a rare genetic disorder that is characterized by an imperforate anus, dysplastic ears, thumb malformations and other abnormalities, such as hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. In addition, the protein tyrosine phosphatase receptor type Q (PTPRQ) gene has been identified in nonsyndromic hearing loss patients with autosomal recessive or autosomal dominant inherited patterns.MethodsA Chinese family with TBS and hearing loss was enrolled in this study. The proband was a two-month-old girl who suffered from congenital anal atresia with rectal perineal fistula, ventricular septal defect, patent ductus arteriosus, pulmonary hypertension (PH), and finger deformities. The proband’s father also had external ear deformity with deafness, toe deformities and PH, although his anus was normal. Further investigation found that the proband’s mother presented nonsyndromic hearing loss, and the proband’s mother’s parents were consanguine married. Whole-exome sequencing and Sanger sequencing were applied to detect the genetic lesions of TBS and nonsyndromic hearing loss.ResultsVia whole-exome sequencing and Sanger sequencing of the proband and her mother, we identified a novel heterozygous mutation (ENST00000251020: c.1428_1429insT, p. K478QfsX38) of SALL1 in the proband and her father who presented TBS phenotypes, and we also detected a new homozygous mutation [ENST00000266688: c.1057_1057delC, p. L353SfsX8)] of PTPRQ in the proband’s mother and uncle, who suffered from nonsyndromic hearing loss. Both mutations were located in the conserved sites of the respective protein and were predicted to be deleterious by informatics analysis.ConclusionsThis study confirmed the diagnosis of TBS at the molecular level and expanded the spectrum of SALL1 mutations and PTPRQ mutations. Our study may contribute to the clinical management and genetic counselling of TBS and hearing loss.

Strategic analysis of a medical genetics center at a national health research institute in Brazil: challenges for the country's public health system.

to discuss strategic challenges in complex health organizations sustained by an analysis in a Medical Genetics Center at a National Health Research Institute in Brazil. Démarche Stratégique adapted for use with research institutes, including the policy formulation function. The study used institution's databases and workshops with key actors between Dec/2014 and Jun/2015. Were defined the segments: clinical diagnosis, lysosomal diseases, osteogenesis imperfecta, genetic counseling, cytogenetics, biochemistry, and genomics. The findings reveal that the segments are aligned with the Institute's mission when it comes to referral care, although investment is required in strategic areas. The clinical diagnosis, lysosomal diseases, and genomics segments stood out in the scientific output portfolio. The findings show that progress needs to be made with policy implementation and planning to improve access to new technologies, together with investment in training and development, and the strengthening of coordination and collaboration between research institutes and referral services and between the wider healthcare network and research, care, and teaching. The inclusion of the policy formulation dimension was essential to highlight the unique role medical genetics plays in Brazil's public health system and the importance of developing action plans in the field of public health.

Animal and cellular models of microphthalmia.

Animal and Cellular Models of the Eye Disorder, Microphthalmia (Small Eye) Microphthalmia, meaning a small, underdeveloped eye, is a rare disorder that children are born with. Genetic changes or variations in the environment during the first 3 months of pregnancy can disrupt early development of the eye, resulting in microphthalmia. Up to 11% of blind children have microphthalmia, yet currently no treatments are available. By understanding the genes necessary for eye development, we can determine how disruption by genetic changes or environmental factors can cause this condition. This helps us understand why microphthalmia occurs, and ensure patients are provided with the appropriate clinical care and genetic counselling advice. Additionally, by understanding the causes of microphthalmia, researchers can develop treatments to prevent or reduce the severity of this condition. Animal models, particularly mice, zebrafish and frogs, which can also develop small eyes due to the same genetic/environmental changes, have helped us understand the genes which are important for eye development and can cause birth eye defects when disrupted. Studying a patient's own cells grown in the laboratory can further help researchers understand how changes in genes affect their function. Both animal and cellular models can be used to develop and test new drugs, which could provide treatment options for patients living with microphthalmia. This review summarises the key discoveries from animal and cellular models of microphthalmia and discusses how innovative new models can be used to further our understanding in the future.

Researchers’ perspectives on return of individual genetics results to research participants: a qualitative study

ABSTRACT Genetic results are usually not returned to research participants in Uganda despite their increased demand. We report on researchers’ perceptions and experiences of return of individual genetic research results. The study involved 15 in-depth interviews of investigators involved in genetics and/or genomic research. A thematic approach was used to interpret the results. The four themes that emerged from the data were the need for return of individual results including incidental findings, community engagement and the consenting process, implications and challenges to return of individual results. While researchers are willing to return clinically significant genetic results to research participants, they remain unsure of how this should be implemented. Suggestions to aid implementation of return of results included reconsenting of participants before receiving individual genetic results and increasing access to genetic counseling services. Community engagement to determine community perceptions and individual preferences for the return of results, and also prepare participants to safely receive results emerged as another way to support return of results. Researchers have a positive attitude toward the return of clinically significant genetic results to research participants. There is need to develop national guidance on genetic research and also build capacity for clinical genetics and genetic counseling.

Physicians' Awareness of the Breast Cancer Survivors' Unmet Needs in Korea.

PurposePhysicians' awareness of their cancer patients' unmet needs is an essential element for providing effective treatment. This study investigated the accuracy of physicians' awareness of breast cancer survivors' unmet needs in Korea.MethodsA cross-sectional interview survey was performed among 106 physicians and 320 Korean breast cancer survivors. The Comprehensive Needs Assessment Tool was administered to physicians and cancer survivors after obtaining their written informed consent to participate. Data were analyzed using t-test, analysis of variance, and multiple regression analysis.ResultsThe level of unmet needs was highest in the hospital service domain (mean ± standard deviation: 2.19 ± 0.82), and the top-ranked unmet need item was “wished my doctor to be easy, specific, and honest in his/her explanation” (2.44 ± 0.93). Higher unmet needs were correlated with the presence of a genetic counseling clinic. They were not associated with age, sex, marital status, religion, department, working period, type of institution, number of staff, and number of operations. In multiple regression analysis, the presence of a genetic counseling clinic was associated with a higher level of recognition for psychological problems, social support, hospital service, and information and education needs. Physicians overestimated breast cancer survivors' unmet needs in all domains, compared to their self-reported unmet needs. The discordance in the perceived unmet needs was highest in the ‘family/personal relationship problems’ domain.ConclusionsPhysicians who treat Korean breast cancer survivors rated the level of unmet needs of breast cancer survivors as highest in the hospital service domain. The presence of a genetic counseling clinic in physicians' institutions was associated with a higher perception of survivors' unmet needs. Physicians overestimated the level of unmet needs in Korean breast cancer survivors. Efforts to reduce these discordances are needed to implement optimal survivorship care.

A novel mutation in ext2 caused hereditary multiple exostoses through reducing the synthesis of heparan sulfate.

Hereditary multiple exostoses (HME) is a rare skeletal disorder characterized by the formation of multiple benign cartilage-capped tumors, usually in the metaphyseal region of the long bones. Over 70% of HME cases arise from monoallelic mutations in either of the two genes encoding the heparan sulfate (HS) synthesis enzymes, ext1 and ext2. To identify more HME-associated mutations, genomic DNA from members of five independent consanguineous families with HME was sequenced with whole exome sequencing (WES). A novel heterozygous splice site mutation (c.1173+2T>A) in ext2 was detected in all three affected members of family V. Further study showed that the novel mutation caused exon 7 of ext2 mRNA to be skipped during splicing and caused a frameshift after the codon for Arg360, which results in the appearance of new 43 codons, followed by a termination codon. Although the resulting truncated protein was still localized to the Golgi, similar to the full-length EXT2, its HS synthesis activity decreased by 40%. In this study, a novel splice site mutation in ext2 was identified and suggested to be a pathogenic mutation of HME, which may expand the genetic etiology spectrum of HME and may be helpful for clinical genetic counseling and prenatal diagnosis.

Huntington’s disease in Turkey: genetic counseling, clinical features, and outcome

ABSTRACT Objective: This study aims to report the data of genetic counseling and to identify the clinical features of Turkish Huntington’s disease (HD) patients and to investigate its possible relationship with genetic data. Method: A regular weekly outpatient clinic has been held routinely since January 2018. Patients and their referred relatives have been evaluated regarding clinical features and genetic counseling. The database of our collaborative team was used for the study. Results: Total 141 individuals have been evaluated. Among 84 subjects genetic counseling was given, diagnosis of HD was confirmed genetically in 34 (42.0%) of individuals (25 were symptomatic-HD, 9 were presymptomatic-HD). Fifty-seven patients were previously diagnosed with HD. The mean age of onset was 42.4 (11.9) years. Chorea was mostly reported initial symptom. The mean CAG repeat number of the expanded allele was 44.1 (5.1) and correlated inversely with the age of onset (p < 0.001). During a 4.8 (3.1) year follow-up, 10% of the patients were deceased. At the last visit, over half of patients had all of the movement, behavioral and cognitive problems, and 41.6% of them had required 24-hr supervision appropriate (UHDRS-independence score 64.6 (24.4)). Paternal inheritance was related to higher CAG repeats, younger age of disease onset, and higher UHDRS-motor scores. Conclusion: HD in Turkey is a severe disabling disease affecting a younger adult population. Over half of patients had all of the movement, behavioral and cognitive problems. Genetic counseling gives the opportunity to diagnose subjects at the pre-symptomatic phase. A collaborative approach is rational in the management of HD.

Large genotype\u2013phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis

Facioscapulohumeral muscular dystrophy (FSHD) is a myopathy with prevalence of 1 in 20,000. Almost all patients affected by FSHD carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Assessment of size of D4Z4 alleles is commonly used for FSHD diagnosis. However, the extended molecular testing has expanded the spectrum of clinical phenotypes. In particular, D4Z4 alleles with 9–10 repeat have been found in healthy individuals, in subjects with FSHD or affected by other myopathies. These findings weakened the strict relationship between observed phenotypes and their underlying genotypes, complicating the interpretation of molecular findings for diagnosis and genetic counseling. In light of the wide clinical variability detected in carriers of D4Z4 alleles with 9–10 repeats, we applied a standardized methodology, the Comprehensive Clinical Evaluation Form (CCEF), to describe and characterize the phenotype of 244 individuals carrying D4Z4 alleles with 9–10 repeats (134 index cases and 110 relatives). The study shows that 54.5% of index cases display a classical FSHD phenotype with typical facial and scapular muscle weakness, whereas 20.1% present incomplete phenotype with facial weakness or scapular girdle weakness, 6.7% display minor signs such as winged scapula or hyperCKemia, without functional motor impairment, and 18.7% of index cases show more complex phenotypes with atypical clinical features. Family studies revealed that 70.9% of relatives carrying 9–10 D4Z4 reduced alleles has no motor impairment, whereas a few relatives (10.0%) display a classical FSHD phenotype. Importantly all relatives of index cases with no FSHD phenotype were healthy carriers. These data establish the low penetrance of D4Z4 alleles with 9–10 repeats. We recommend the use of CCEF for the standardized clinical assessment integrated by family studies and further molecular investigation for appropriate diagnosis and genetic counseling. Especially in presence of atypical phenotypes and/or sporadic cases with all healthy relatives is not possible to perform conclusive diagnosis of FSHD, but all these cases need further studies for a proper diagnosis, to search novel causative genetic defects or investigate environmental factors or co-morbidities that may trigger the pathogenic process. These evidences are also fundamental for the stratification of patients eligible for clinical trials. Our work reinforces the value of large genotype–phenotype studies to define criteria for clinical practice and genetic counseling in rare diseases.

Suicide in frontotemporal dementia and Huntington disease: analysis of family-reported pedigree data and implications for genetic healthcare for asymptomatic relatives

Objective Genomic testing for early-onset dementia is becoming more accessible, along with predictive testing for at-risk relatives; however, complex counselling issues are important to address. The topic of suicide often has stigma associated, and thoughts or experiences may not be volunteered without prompting. Little has been published with consideration to suicide rates in the context of family experiences and their significance in genetic counselling for relatives of people with Huntington disease and frontotemporal dementia. Design This study included pedigree information for 267 symptomatic individuals with frontotemporal dementia or Huntington disease, provided via genetic counselling clinics. Main Outcome Measures Descriptive statistics and suicide rate calculations based on family reported pedigree data. Results The suicide rate was 2996 per 100,000 compared with the population rate of 10 per 100,000. Approximately one in 15 families reported suicide of an affected family member, and file notes indicated that one in five families had experienced suicide, suicidal thoughts or suicide attempts in one or more affected, unaffected or pre-symptomatic relative. Conclusion Health professional awareness of family experiences, including suicide of a relative, is vital in facilitating client decisions about genetic testing, and in providing adequate psychosocial support during the process of genetic testing and adaption to results.

Identification and computational analysis of USH1C, and SLC26A4 variants in Pakistani families with prelingual hearing loss.

Hearing loss (HL) is clinically and genetically heterogeneous disorder and is the most frequent occurring sensory deficit in humans. This study was conducted to decipher the genetic cause of HL occurring in two large consanguineous Pakistani families (GCNF-01, GCNF-03). Family history and pure tone audiometry of both families suggested prelingual HL, while the affected individuals of GCNF-01 also had low vision and balance problems, consistent with cardinal features of Usher syndrome type I (USH1). Exome sequencing followed by segregating analysis revealed a novel splice site variant (c.877-1G > A) of USH1C occurring with USH1 phenotype in family GCNF01. While the affected individual of family GCNF-03 were homozygous for the c.716T > A, p.(Val239Asp) previously reported pathogenic variant of SLC26A4. Both variants have very low frequencies in control database. In silico mutagenesis and 3-dimensional simulation analyses revealed that both variants have deleterious impact on the proteins folding and secondary structures. Our study expands the mutation spectrum of the HL genes and emphasizes the utility of exome sequencing coupled with bioinformatics tools for clinical genetic diagnosis, prognosis, and family counseling.