Clinical Genetic Counseling Research Articles

Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the PTPRQ Gene Causing Autosomal Recessive Hearing Loss in a Chinese Family.

Hearing loss is among the most common congenital sensory impairments. Genetic causes account for more than 50% of the cases of congenital hearing loss. The PTPRQ gene, encoding protein tyrosine phosphatase receptor Q, plays an important role in maintaining the stereocilia structure and function of hair cells. Mutations in the PTPRQ gene have been reported to cause hereditary sensorineural hearing loss. By using next-generation sequencing and Sanger sequencing, we identified a novel compound heterozygous mutation (c.997 G > A and c.6603-3 T > G) of the PTPRQ gene in a Chinese consanguineous family. This is the first report linking these two mutations to recessive hereditary sensorineural hearing loss. These findings contribute to the understanding of the relationship between genotype and hearing phenotype of PTPRQ-related hearing loss, which may be helpful to clinical management and genetic counseling.

Three Variants Affecting Exon 1 of Ectodysplasin A Cause X-Linked Hypohidrotic Ectodermal Dysplasia: Clinical and Molecular Characteristics.

Background: Ectodysplasin A (EDA) variations are major pathogenic factors for hypohidrotic ectodermal dysplasia (HED), the most common form of ectodermal dysplasia (ED), characterized by hypotrichosis, hypohidrosis, hypodontia, and other oral features. Methods: Molecular genetic defects in three HED families were detected by whole-exome sequencing and confirmed by Sanger sequencing or multiplex ligation-dependent probe amplification. The effect of splicing variant was further verified by EDA minigene in vitro analysis. De novo deletion was confirmed by chromosomal microarray analysis. Results: Three variants (c.396 + 1 G > C, c.171-173 del GTT, and exon 1 deletion) were identified, all affecting exon 1 of the EDA gene. Variants c.396 + 1 G > C and c.171-173 del GTT were first identified. Minigene analysis of the splicing variant (c.396 + 1 G > C) displayed a prolonged EDA-A1 transcript containing extra 699 bp at the start of intron 1, representing a functional cryptic splice site formation in vitro. Combining the results of chromosomal microarray analysis and whole-exome sequencing, the deletion variant was over 87 kb. Three variants were predicted to affect protein function to differing degrees, and were responsible for X-linked HED with varying phenotype. Conclusion: Investigating the clinical and molecular characteristics of these variations broadens our understanding of EDA gene variants, supporting clinical diagnosis, genetic counseling, and prenatal diagnosis of HED.

Evaluating a general pediatric/adult genetic counseling clinic in a Midwest medical center.

In 2018, the Munroe-Meyer Institute for Genetics & Rehabilitation (MMI) at the University of Nebraska Medical Center (UNMC) in Omaha, NE created a genetic counseling clinic (GCC) to increase access to genetics services and decrease the time spent between a referral and being seen in a general genetics outpatient clinic. In the GCC, genetic counselors led patient encounters and geneticists served as advisors, rather than primary providers. We conducted a chart review of 109 patients seen in the GCC from November 1, 2018, to March 16, 2020, and obtained information regarding patient demographics, indications, and clinical recommendations as a result of the visit. Most patients seen in this clinic were female (65.1%) and aged 19 years of age or older (54.1%). The primary indications for patients in this clinic included review genetic test results (42.2%), coordination of genetic testing for a known familial variant (30.2%), and concerns for personal or family history suspicious of a genetic condition without dysmorphic features (24.8%). The average patient wait time between referral date and appointment date in the GCC was 49.8 days. The two most common clinical recommendations made by genetic counselors in the GCC were genetic testing (56.1%) and/or follow-up with specialist (26.5%). These specialists primarily included endocrinology (n=5), neurology (n=4), cardiology (n=4), ophthalmology (n=3), and audiology (n=3). We found that the GCC model may be appropriate for patients with (1) genetic test results requiring interpretation, (2) a known familial variant or (3) genetic testing recommended by a specialist physician. Descriptions of the indications and recommendations for patients seen in this GCC provide a framework for potential implementation of a GCC in other regions across the nation.

Analysis of pathogenic gene variant in two children with Treacher-Collins syndrome

To explore the clinical and genetic characteristics of two children with a clinical diagnosis of Treacher Collins syndrome (TCS). Whole-exome sequencing was used to screen potential variants in the two children. Confirmation of suspected variants was performed through Sanger sequencing, multiplex ligation dependent probe amplification and real-time PCR in probands and their parents. A heterozygous deletion variant, c.4357_4360delGAAA, was detected in case one, while was de novo and verified by Sanger sequencing. The variant was classified as pathogenic (PVS1 +PM2+PM6) according to ACMG guideline. The heterozygous deletion of exon 1-7 was seen in the same gene in case 2, which MLPA verified as heterozygous deletion of exon 1-6. This deletion was inherited from the father with a normal phenotype, and the father's TCOF1 gene was suspected to be chimeric heterozygous deletion of exon 1-6 verified by MLPA. The identified variants in the TCOF1 gene probably underlie the two cases of TCS. There was no apparent correlation between genotype and phenotype. In addition, it shows a high interfamilial variability ranging from normal to full presentation of TCS. Genetic detection provided clinical diagnosis and genetic counselling for TCS patients.

Global Expansion of Jeffrey's Insights: Jeffrey Modell Foundation's Genetic Sequencing Program for Primary Immunodeficiency.

Genetic disorders that impair the immune system, known as Primary Immunodeficiencies (PI), include over 450 single-gene inborn errors of immunity. Timely and appropriate diagnosis and treatment is vital to quality of life (QOL) and sometimes survival, as patients are susceptible to frequent, persistent, severe, and sometimes life-threatening infections or autoimmunity. Suspected PI patients that do not have a genetic diagnosis often endure a prolonged, onerous, inefficient, and expensive experience, known as a diagnostic odyssey. The resulting diagnostic delay prohibits proper disease management and treatment, causing unnecessary distress and diminished QOL. Next-generation sequencing (NGS) offers relief from the distress of the diagnostic odyssey, but because of cost and barriers to access, it is regularly unobtainable. The Jeffrey Modell Foundation (JMF) introduced “Jeffrey’s Insights”, a no-charge genetic sequencing pilot program, in January 2019 for patients within the Jeffrey Modell Centers Network (JMCN) with an underlying PI, but no genetic diagnosis. Building on the success of the pilot program, JMF expanded it globally to more than 400 Centers in the JMCN in early 2020. The most current version of Invitae’s PI Panel available was used for this program. All participating clinicians were invited to complete a brief questionnaire assessing prior impediments to access and post-sequencing alterations in disease management and treatment. A total of 1,398 patients were tested, with 20.3% receiving a molecular diagnosis and many more receiving helpful diagnostic leads. Results obtained from genetic sequencing led to an alteration of clinical diagnosis, disease management, treatment, and genetic counseling in 39%, 38%, 35%, and 53% of patients, respectively. The global expansion of this program further underscores the crucial need for NGS for PI, along with its efficiency and potential cost savings. The results of this program to date further define rationale for the availability of comprehensive diagnostic NGS for patients with PI when requisitioned by an expert immunologist.

H1299R Variant in Factor V and Recurrent Pregnancy Loss: A Systematic Review and Meta-Analysis Protocol.

Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies, affecting approximately 1 to 3% of women worldwide. Scientific data highlight a possible correlation between thrombophilic genetic variants and RPL. H1299R variant in the factor V gene would lead to an increased thrombotic risk associated with frequent miscarriages. However, the data are often conflicting, making this an interesting question for further investigations by evaluating genotype-phenotype correlations to improve the clinical management and genetic counseling of couples. A systematic review and meta-analysis will follow the preferred reporting elements for systematic review and meta-analysis protocols (PRISMA-P). The Pubmed (MEDLINE) and Embase (OVID) databases will be explored to identify suitable articles based on inclusion and exclusion criteria. Inclusion criteria are: (a) H1299R genotyping with clear data reported, referred to as Heterozygous (Het) and/or Homozygous (Hom); (b) articles written in English; (c) analyses of only RPL female patients having at least two or more previous pregnancy losses and compared with a control group. This analysis will present selected scientific evidence, addressing the questions concerning the association between the H1299R variant and RPL, hoping to clarify this still unresolved issue. PROSPERO registration number: CRD42022330077.

NFB-01. Central nervous system tumors in Von Hippel-Lindau multisystem disorder: are there preventive approaches to escape tumor initiation at a young age?

In pediatric neuro-oncology, the likelihood of an underlying tumor predisposition condition should be considered for all types of brain tumors. The aim of this study was to report the dramatic history of a VHL Tunisian family with many affected adolescents presenting central nervous system hemangioblastomas among wich many died in their twenties and those who survived suffered from depression and suicide attempts. To provide optimal clinical care and genetic counseling to affected patients and their young relatives, we conducted a literature review to answer the major question for this family: are there any preventive approaches to escape tumor initiation in our at-risk relatives at young age? The onset of VHL syndrome at the index case of our Tunisian family was at the age of 40 years when she presented a blurred vision on the right, related to retinal angiomatosis. The evolution was caraterised by recurrent eye lesions, the development of multiple renal tumors and hemangioblastomas at the cerebral, cerebellar and cervical spinal cord levels with neurologic symptoms and various functional nervous sequels after neurosurgical resections. Familial features of VHL were present in half of her siblings (6 among 12). Her 2 adolescent sisters, dead at the age of 20, harbored cerebral hemangioblastomas, whereas 2 of her brothers who died respectively at the age of 21 and 47 years harbored respectively ocular angiomas and vertebral angiomas. A third 48 year-old alive brother harbored cerebral hemangioblastoma as well as renal cell carcinoma. Only preimplantation genetic diagnosis (PGD) to select unaffected embryos can be applied to prevent the disease. High-throughput methods such as microarrays and sequencing are available nowadays for late-onset disorders with genetic predispositions. Long term surveillance and timely preventive treatment of lesions are crucial for VHL disease carriers. Effective psychosocial support to vulnerable children and their families is also essential.

Natural history study for children and adults with rare solid tumors.

TPS1600 Background: Rare cancers is defined as fewer than 15 cases per 100,000 people per year and account for 27% cancers diagnosed and lead to 25% of cancer-related deaths. Nearly 13% (1 in 8) of all cancers diagnosed in adults ages 20 and older are rare. All pediatric cancers are rare and approximately 12,600 children under the age of 20 years are diagnosed with cancer each year. Rarity of these diseases has caused a stagnation in understanding the tumor biology and developing newer therapies. Initiatives like Orphan Drug Act (1983) and Rare Disease Act (2002) has led to improvement in funding and research about these rare tumors. The Cancer Moonshot Research Initiative funded My Pediatric and Adult Rare Tumor (MyPART) network (cancer.gov/mypart) in the NCI Pediatric Oncology Branch and launched a longitudinal Natural History Study for Children and Adults with Rare Solid Tumors (NCT03739827). Methods: A prospective study to evaluate the natural history of rare pediatric and adult solid tumors comprehensively and longitudinally. Patients of any age with a rare solid tumor (<15 cases per 100,000 people per year) are eligible. Patients with germline mutation who are at risk of developing these tumors or relatives of participants are also eligible. Patients can participate from home or are are invited to NIH for annual evaluations. Participants complete individual medical history, family history, patient related-outcomes measurements (PROs) and provide samples (blood, saliva) for DNA analysis. Tumors are analyzed using a 500+ gene panel (TruSight500, Illumina Panel) and undergo a comprehensive genomic and epigenomic analysis. Participants invited to NIH undergo a clinical evaluation, genetic counseling, blood collection (standard clinical labs, germline DNA/RNA, immune phenotypes, cytokines, exosomes), and imaging studies, as indicated. The goals of this study are to 1) Estimate and define the clinical spectrum of rare cancers 2) Evaluate and follow biological relatives of patients with rare tumors or carriers of germline genetic variants that predispose to development of rare tumors 3) Develop a better understanding of these diseases in an effort to develop a) Novel therapeutic interventions, b) Preventive/screening guidelines, c) Endpoints for future clinical trials, and d) Relevant patient reported outcomes that can improve our understanding of patients psychosocial and functional needs. Subprotocols under this protocol for children and adults include adrenocortical cancer (NCT04447014), neuroendocrine neoplasms (NCT04488263) and Chordoma (NCT0391046) to gather tumor specific data. Study accrual is ongoing. Clinical trial information: NCT03739827.

Multiple endocrine neoplasia type 1 caused by mosaic mutation: clinical follow-up and genetic counseling?

MEN1 is an autosomal dominant hereditary syndrome characterized by several endocrine tumors, in most cases affecting the parathyroid glands, pancreas, and anterior pituitary. It is the result of inactivating mutations in the tumor suppressor gene MEN1. More than 1300 different mutations have been identified in this gene. Mosaic MEN1 mutations have been previously described in only a few patients in the literature. In this paper, we provide a review of six cases of MEN1 mosaicism reported in the literature supplemented with six additional cases described by the French TENgen network of laboratories. This review highlights that (i) MEN1 mosaicism is not associated with a mild phenotype and results in the same natural history as heterozygous MEN1 mutation and (ii) that more systematic detection of MEN1 mosaic mutation enables improvements in both patient monitoring and genetic counseling.

Frequency of Different Types of Endothelial Corneal Dystrophies by Age, Gender, and Visual Acuity in Punjab, Pakistan

Endothelial Corneal Dystrophy (ECD) is, by definition, an endogenous degeneration that progresses slowly in the corneal endothelium as a result of genetic predisposition. A transverse study was conducted from September 2018 to June 2019, and the subjects affected with ECD were examined by visiting various city hospitals in Punjab including Sahiwal, Narowal, Okara, Gujranwala, Kasur, Lahore, and Multan. The basic objective of the current investigation was to find the frequency of different types of ECD in the population of different cities in Punjab. Data was collected based on relevant parameters such as age, gender, and visual acuity. The visual acuity was assessed by ophthalmologists via Snellen chart and Visual acuity test. Among 3000 patients, 6.6 % (n=198) cases of ECD were recognized which includes more males 52.52 % (n=104) as compared to females 47.48 % (n=94). Maximum cases of ECD 31.82 % (n=63) were observed in the 41-50 years of age group. In all types of ECD, FECD was observed most abundant with 38.38 % (n=76) and XECD with the least abundance of 6.67 % (n=13). The frequency of CHED and PPCD was 25.25 % (n=50) and 29.79 % (n=59) respectively. The results of recent research finalize that endothelial corneal dystrophy is a rare disease prevailing in Pakistan with a proportion of only 6.6 %. This study benefits in updating the data about the frequency of endothelial corneal dystrophy in Pakistan. Careful clinical evaluation, initial diagnosis, genetic counseling, genotyping, and correct treatment are necessary for the restoration of vision loss due to ECD.

Clinical and genetic analysis of a child with mental retardation autosomal dominant 7

To analyze the clinical and genetic characteristics of a child with clinical manifestations of hypoplasia, epilepsy and abnormal face. The clinical data of the child were collected. The peripheral blood samples of the patient and his parents were extracted for high-throughput sequencing, and Sanger sequencing verification and bioinformatics analysis were performed to detect suspected pathogenic variants. The clinical manifestations of the child were overall developmental backwardness, seizures, autism, and special facial appearance. High throughput sequencing showed that there was a heterozygous mutation of exon 11: c.1920_c.1927delCCTCTACC (p.Ser641Rfs*31) of the DYRK1A gene. The same variant was found in neither of her parents, suggesting that it has a denovo origin. The exon11: c.1920_c.1927delCCTCTACC (p.Ser641Rfs*31) mutation in DYRK1A gene was the genetic etiology of the case, which enriches the pathogenic gene spectrum of DYRK1A and provides the basis for clinical diagnosis and genetic counseling.

Perspectives on Consumer and Clinical Genetic Testing Education among Medical Students in West Texas.

There is a popular trend for genetic test companies to market genetic screenings to identify detrimental mutations directly to consumers. As a result, there has been an increase in the number of patients wanting to discuss the results of their personal genetic tests with their physician. In turn, the medical education community has recognized a need to provide medical staff and patients with resources to interpret and act on personal genetic data. Most medical students and residents lack the requisite knowledge to interpret and manage patient-provided individualized genetic testing. This has prompted a growing interest among medical students in learning more about genetic testing and how to counsel their patients on this information. Consequently, early educational exposure to clinical genetic testing and counseling would benefit medical education training programs. In this study, we examine the perceptions of medical students in West Texas with regard to clinical genetic testing.

PD11-07 AWARENESS OF RISK OF PROSTATE CANCER (PCA) REMAINS POOR IN FAMILIES WITH GERMLINE MUTATIONS IN DNA-REPAIR GENES

You have accessJournal of UrologyCME1 May 2022PD11-07 AWARENESS OF RISK OF PROSTATE CANCER (PCA) REMAINS POOR IN FAMILIES WITH GERMLINE MUTATIONS IN DNA-REPAIR GENES Giuseppe Chiarelli, Rodolfo Hurle, Paolo Casale, Alberto Saita, Giovanni Lughezzani, Vittorio Fasulo, Alessio Benetti, Giorgio Guazzoni, Massimo Lazzeri, NicolòMaria Buffi, Monica Zuradelli, and Massimo Lazzeri Giuseppe ChiarelliGiuseppe Chiarelli More articles by this author , Rodolfo HurleRodolfo Hurle More articles by this author , Paolo CasalePaolo Casale More articles by this author , Alberto SaitaAlberto Saita More articles by this author , Giovanni LughezzaniGiovanni Lughezzani More articles by this author , Vittorio FasuloVittorio Fasulo More articles by this author , Alessio BenettiAlessio Benetti More articles by this author , Giorgio GuazzoniGiorgio Guazzoni More articles by this author , Massimo LazzeriMassimo Lazzeri More articles by this author , NicolòMaria BuffiNicolòMaria Buffi More articles by this author , Monica ZuradelliMonica Zuradelli More articles by this author , and Massimo LazzeriMassimo Lazzeri More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002537.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: About 5-10% of PCa correlate with an inherited susceptibility. Germline mutations in DNA-repair genes (DRG) were found in approximately 5% of localized PCa and in 12% of metastatic castration-resistant PCa. As DRG mutations correlate with PCa aggressiveness there is an urgent need to test individuals suspected to be carriers who most benefit from early diagnosis and personalized therapies. The aim of the present study is to investigate the awareness of risk of PCa in families with germline mutations in DRG. METHODS: This is a prospective, monocentric study of families with DRG mutations. Those families ere selected from all families of women with breast and/or ovarian cancer treated in the last 5 years at the Breast Unit of our tertiary University Hospital. To test the awareness of risk of PCa we used the ratio between the number of families (where at least one man was present, who was offered the test for mutation detection) and probands who were really tested. Willingness to be tested was stratified according demographic, educational status and geographical residence. Healthy men with DRG mutations were offered a dedicated annual PCa screening consisting of digital rectal examination (DRE), blood test for Prostate Health Index (PHI) and multiparametric MRI with software assisted target biopsy plus systematic biopsy in suspected cases. RESULTS: Reviewing the genealogical trees of all breast/ovarian cancer patients who attended our Genetic Counselling Clinic from January 2016 to May 2021, we identified, over 1083 families, 132 positive ones for mutations in DRG. Over 132 families, we found that all the male members of 62 rejected to be tested. The original parent branch of mutation was unknown in 24 families and limited the interest in male relatives. In 9 families no male relatives were present; in 5 families, all men were already tested negative; probands were missed in 8. Finally, we selected 29 families (25%) with at least one male relative willing to be tested. We identified 59 men with a DRG mutation, of whom 27 met the inclusion criteria for screening and started it. Living in Northern Italy, higher educational levels, being married, the presence of offspring and at least one first-degree relative affected with cancer correlated with a higher willingness to be tested (p <0.05). No correlation between age at genetic counselling and test acceptance was found. CONCLUSIONS: Our analysis showed that only 25% of men with a high-risk of developing PCa accepted a genetic profiling, limiting their access to a dedicated PCa screening. This observation strongly supports the urgent need to implement awareness of genetic risk for PCa within male population. Source of Funding: This work was supported by AIRC (Associazione Italiana Ricerca sul Cancro), grant number IG 2020 ID 25027 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e192 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Giuseppe Chiarelli More articles by this author Rodolfo Hurle More articles by this author Paolo Casale More articles by this author Alberto Saita More articles by this author Giovanni Lughezzani More articles by this author Vittorio Fasulo More articles by this author Alessio Benetti More articles by this author Giorgio Guazzoni More articles by this author Massimo Lazzeri More articles by this author NicolòMaria Buffi More articles by this author Monica Zuradelli More articles by this author Massimo Lazzeri More articles by this author Expand All Advertisement PDF DownloadLoading ...

Identification of a New Mutation p.P88L in Connexin 50 Associated with Dominant Congenital Cataract.

Congenital hereditary cataract is genetically heterogeneous and the leading cause of visual impairment in children. Identification of hereditary causes is critical to genetic counselling and family planning. Here, we examined a four-generation Chinese pedigree with congenital dominant cataract and identified a new mutation in GJA8 via targeted exome sequencing. A heterozygous missense mutation c.263C > T, leading to a proline-to-Leucine conversion at the conserved residue 88 in the second transmembrane domain of human connexin 50 (Cx50), was identified in all patients but not in unaffected family members. Functional analyses of the mutation revealed that it disrupted the stability of Cx50 and had a deleterious effect on protein function. Indeed, the mutation compromised normal membrane permeability and gating of ions, and impeded cell migration when overexpressed. Together, our results expand the pathogenic mutation spectrum of Cx50 underlying congenital cataract and lend more support to clinical diagnosis and genetic counseling.

An internship in psychiatric genetic counseling: Impact on genetic counseling graduates' practice and career choices.

Though psychiatric genetic counseling has been shown to have meaningful positive impacts on patient outcomes, there is currently only one specialist psychiatric genetic counseling clinic (located in Vancouver, BC). The service is inconsistently offered elsewhere, leaving this patient population largely underserved. In an effort to expand psychiatric genetic counseling, the clinic in Vancouver has been providing specialist internship training to genetic counseling students since 2012. This study explored the impact of the internship training on genetic counseling graduates' careers. Using an interpretive description approach, we recorded and transcribed interviews with past interns. Coding and data analysis were conducted concurrently. The interview guide was iteratively revised through the interview process and memoing was used to record ideas about the data and interviews throughout. From interviews with 15 past interns, we generated a theoretical model-'a fragile dream, easily broken'-describing the impact of the training on participants' careers. Completing an internship in psychiatric genetic counseling positively influenced participants' desire to provide psychiatric genetic counseling; however, most were unable to find work in the subspecialty. Some participants made efforts to create specialist positions for themselves, but setbacks and hurdles left many feeling defeated, resulting in them accepting established roles in other disciplines. We contextualize our findings in a discussion of what may be needed in order to successfully expand psychiatric genetic counseling.

Genome-wide sequencing and the clinical diagnosis of genetic disease: The CAUSES study.

SummaryGenome-wide sequencing (GWS) is a standard of care for diagnosis of suspected genetic disorders, but the proportion of patients found to have pathogenic or likely pathogenic variants ranges from less than 30% to more than 60% in reported studies. It has been suggested that the diagnostic rate can be improved by interpreting genomic variants in the context of each affected individual’s full clinical picture and by regular follow-up and reinterpretation of GWS laboratory results.Trio exome sequencing was performed in 415 families and trio genome sequencing in 85 families in the CAUSES study. The variants observed were interpreted by a multidisciplinary team including laboratory geneticists, bioinformaticians, clinical geneticists, genetic counselors, pediatric subspecialists, and the referring physician, and independently by a clinical laboratory using standard American College of Medical Genetics and Genomics (ACMG) criteria. Individuals were followed for an average of 5.1 years after testing, with clinical reassessment and reinterpretation of the GWS results as necessary. The multidisciplinary team established a diagnosis of genetic disease in 43.0% of the families at the time of initial GWS interpretation, and longitudinal follow-up and reinterpretation of GWS results produced new diagnoses in 17.2% of families whose initial GWS interpretation was uninformative or uncertain. Reinterpretation also resulted in rescinding a diagnosis in four families (1.9%). Of the families studied, 33.6% had ACMG pathogenic or likely pathogenic variants related to the clinical indication. Close collaboration among clinical geneticists, genetic counselors, laboratory geneticists, bioinformaticians, and individuals’ primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS.

Health Supervision for Children and Adolescents With Down Syndrome.

Health Supervision for Children and Adolescents With Down Syndrome.

Demographic Differences Among US Department of Veterans Affairs Patients Referred for Genetic Consultation to a Centralized VA Telehealth Program, VA Medical Centers, or the Community

Telehealth enables access to genetics clinicians, but impact on care coordination is unknown. To assess care coordination and equity of genetic care delivered by centralized telehealth and traditional genetic care models. This cross-sectional study included patients referred for genetic consultation from 2010 to 2017 with 2 years of follow-up in the US Department of Veterans Affairs (VA) health care system. Patients were excluded if they were referred for research, cytogenetic, or infectious disease testing, or if their care model could not be determined. Genetic care models, which included VA-telehealth (ie, a centralized team of genetic counselors serving VA facilities nationwide), VA-traditional (ie, a regional service by clinical geneticists and genetic counselors), and non-VA care (ie, community care purchased by the VA). Multivariate regression models were used to assess associations between patient and consultation characteristics and the type of genetic care model referral; consultation completion; and having 0, 1, or 2 or more cancer surveillance (eg, colonoscopy) and risk-reducing procedures (eg, bilateral mastectomy) within 2 years following referral. In this study, 24 778 patients with genetics referrals were identified, including 12 671 women (51.1%), 13 193 patients aged 50 years or older (53.2%), 15 639 White patients (63.1%), and 15 438 patients with cancer-related referrals (62.3%). The VA-telehealth model received 14 580 of the 24 778 consultations (58.8%). Asian patients, American Indian or Alaskan Native patients, and Hawaiian or Pacific Islander patients were less likely to be referred to VA-telehealth than White patients (OR, 0.54; 95% CI, 0.35-0.84) compared with the VA-traditional model. Completing consultations was less likely with non-VA care than the VA-traditional model (OR, 0.45; 95% CI, 0.35-0.57); there were no differences in completing consultations between the VA models. Black patients were less likely to complete consultations than White patients (OR, 0.84; 95% CI, 0.76-0.93), but only if referred to the VA-telehealth model. Patients were more likely to have multiple cancer preventive procedures if they completed their consultations (OR, 1.55; 95% CI, 1.40-1.72) but only if their consultations were completed with the VA-traditional model. In this cross-sectional study, the VA-telehealth model was associated with improved access to genetics clinicians but also with exacerbated health care disparities and hindered care coordination. Addressing structural barriers and the needs and preferences of vulnerable subpopulations may complement the centralized telehealth approach, improve care coordination, and help mitigate health care disparities.

Clinical and genetic analysis of a Chinese pedigree affected with Dyggve-Melchior-Clausen syndrome due to a novel frameshift variant of DYM gene

To explore the genetic basis of a Chinese pedigree affected with Dyggve-Melchior-Clausen syndrome. Whole exome sequencing and Sanger sequencing were carried out to detect potential pathogenic variants associated with the syndrome. The function of candidate variant was verified by Western blotting. A novel homozygous variant, c.1222delG of the DYM gene was detected in the two affected siblings, for which both parents were heterozygous carriers. The variant has caused replacement of Asp by Met at amino acid 408 and generate a premature stop codon p.Asp408Metfs*10. Western blotting confirmed that the variant can result in degradation of the mutant DYM protein, suggesting that it is a loss of function variant. The homozygous c.1222delG frameshift variant of the DYM probably underlay the Dyggve-Melchior-Clausen syndrome in the two affected siblings. Above findings has enabled clinical diagnosis and genetic counseling for the family.

Identification of a Novel 15q21.1 Microdeletion in a Family with Marfan Syndrome.

Background Marfan syndrome (MFS) is a connective tissue disease involving multiple systems, with thoracic aortic aneurysm (TAA) as the most common life-threatening manifestation. Method A pedigree with TAA was investigated, and peripheral venous blood was extracted from six family members. After whole exome sequencing (WES) and chromosomal microarray analysis (CMA) in these individuals, bioinformatics and inheritance analyses were performed. Result WES revealed a novel, small, 0.76 Mb microdeletion in 15q21.1, which cosegregated with the disease phenotype in the family and led to the haploinsufficiency of the fibrillin 1 (FBN1) gene, which is associated with MFS. This small copy number variant (CNV) was confirmed by CMA. Conclusion Our study expands the phenotypic spectrum of the pathogenic CNV associated with MFS, thereby facilitating clinical genetic diagnosis and future genetic counseling for this family.