Clinical Genetic Counseling Research Articles

How Psychophysical Stress Can Mediate the Effects of Anxiety and Depression on the Overall Quality of Life and Well-Being in Women Undergoing Hereditary Breast Cancer Screening

Background: Women undergoing genetic counseling for hereditary breast cancer often experience a high emotional burden. Distress and stress in the initial phases of genetic counseling can be significant predictors of long-term psychological health, influencing quality of life and well-being. Objectives: This study aimed to evaluate the mediating role of psychophysical stress in the relationship of anxiety and depression with quality of life and well-being in women undergoing genetic counseling for BRCA1/2 mutations. Methods: A sample of 193 women from two genetic counseling clinics was assessed using validated questionnaires measuring the psychological variables under study. Sociodemographic and clinical characteristics were also considered. Results: The results of path analyses indicated a mediating role of psychophysical stress on the relationship between emotional distress and mental quality of life and well-being: higher levels of anxiety and depression were associated with increased psychophysical stress, which, in turn, was linked to a reduced perceived mental quality of life and well-being. Depression was the only significant psychological predictor of physical quality of life. Conclusions: These findings indicate that addressing both anxiety and depression in genetic counseling is crucial for enhancing mental and overall well-being. Interventions should focus on stress management to improve the quality of life, emphasizing depression treatment to enhance physical health outcomes.

Neurologists’ understanding of reproductive medicine options for genetic forms of motor neuron disease

Objectives To examine the knowledge, confidence and practice of motor neuron disease (MND) clinicians toward discussing reproductive options with people who carry a causal variant in an MND gene (both clinically affected and asymptomatic). Methods An online cross-sectional survey was distributed nationwide to UK MND clinicians and clinical geneticists and genetic counselors. The survey assessed respondents’ understanding on reproductive medicine techniques; their confidence in discussing reproductive medicine options and their access to information resources. Results Seventy six clinicians responded to the online survey (45 neurology clinicians and 31 clinical geneticists). MND clinicians had limited knowledge and low confidence in discussing reproductive medicine options. Geneticists were more likely to carry out reproductive genetic counseling with very few MND clinicians reporting undertaking these discussions. Further, 57% of the 45 MND clinicians surveyed reported to have never made a referral for reproductive genetic counseling. Multiple barriers to offering reproductive counseling or referral were identified including a lack of knowledge, lack of awareness of the different options, lack of clinic time and uncertainty around issues such as funding for PGT and whose responsibility it comes under. Conclusions There is a need for training and education on reproductive options and referral for these options needs to be integrated within the health system. Developing more resources for both clinicians and patients is required as MND clinicians reported a lack of resources.

8393 Low Polygenic Risk Score For Autoimmune Addison’s Disease Identifies Misdiagnosed Cases of Monogenic Primary Adrenal Insufficiency

Abstract Disclosure: M. Aranda Guillen: None. I. Botusan: None. V. Fernando: None. E. Røyrvik: None. A. Bøe Wolff: None. S. Johansson: None. E.S. Husebye: None. S. Bensing: None. O. Kampe: None. D. Eriksson: None. Background: Primary adrenal insufficiency (PAI) is sometimes misdiagnosed as autoimmune Addison's disease (AAD), affecting clinical management and genetic counselling. We tested a polygenic risk score (PRS) for AAD (PRS14AAD) as a tool to reevaluate disease etiology and identify patients misdiagnosed with AAD. Methods: We calculated the PRS14AAD in a cohort of patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n=124). Patients with low genetic susceptibility to AAD were selected for whole-genome sequencing to detect potential monogenic causes (n=35). Results: Among the 35 patients, monogenic PAI was diagnosed in 5 (14%) and suspected in 3 additional cases (9%). Three out of the 5 patients diagnosed with monogenic PAI developed the disease in adulthood, indicating late-onset monogenic disease associated with hypomorphic genetic variants. Conclusion: A PRS for AAD can help identify potential monogenic cases, regardless of the age at diagnosis. Early identification of the underlying cause of PAI enables accurate management and correct genetic counselling. Presentation: 6/2/2024

HNF1B Transcription Factor: Key Regulator in Renal Physiology and Pathogenesis.

The HNF1B gene, located on chromosome 17q12, encodes a transcription factor essential for the development of several organs. It regulates the expression of multiple genes in renal, pancreatic, hepatic, neurological, and genitourinary tissues during prenatal and postnatal development, influencing processes such as nephrogenesis, cellular polarity, tight junction formation, cilia development, ion transport in the renal tubule, and renal metabolism. Mutations that alter the function of Hnf1b deregulate those processes, leading to various pathologies characterized by both renal and extrarenal manifestations. The main renal diseases that develop are polycystic kidney disease, hypoplastic or dysplastic kidneys, structural abnormalities, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), and electrolyte imbalances such as hyperuricemia and hypomagnesemia. Extrarenal manifestations include Maturity-Onset Diabetes of the Young (MODY), hypertransaminasemia, genital and urinary tract malformations, Autism Spectrum Disorder (ASD), and other neurodevelopmental disorders. Patients with HNF1B alterations typically carry either punctual mutations or a monoallelic microdeletion in the 17q12 region. Future research on the molecular mechanisms and genotype-phenotype correlations in HNF1B-related conditions will enhance our understanding, leading to improved clinical management, genetic counseling, monitoring, and patient care.

EDA Variants Are Responsible for Approximately 90% of Deciduous Tooth Agenesis

Deciduous tooth agenesis is a severe craniofacial developmental defect because it affects masticatory function from infancy and may result in delayed growth and development. Here, we aimed to identify the crucial pathogenic genes and clinical features of patients with deciduous tooth agenesis. We recruited 84 patients with severe deciduous tooth agenesis. Whole-exome and Sanger sequencing were used to identify the causative variants. Phenotype–genotype correlation analysis was conducted. We identified 54 different variants in 8 genes in 84 patients, including EDA (73, 86.9%), PAX9 (2, 2.4%), LRP6 (2, 2.4%), MSX1 (2, 2.4%), BMP4 (1, 1.2%), WNT10A (1, 1.2%), PITX2 (1, 1.2%), and EDARADD (1, 1.2%). Variants in ectodysplasin A (EDA) accounted for 86.9% of patients with deciduous tooth agenesis. Patients with the EDA variants had an average of 15.4 missing deciduous teeth. Mandibular deciduous central incisors had the highest missing rate (100%), followed by maxillary deciduous lateral incisors (98.8%) and mandibular deciduous lateral incisors (97.7%). Our results indicated that EDA gene variants are major pathogenic factors for deciduous tooth agenesis, and EDA is specifically required for deciduous tooth development. The results provide guidance for clinical diagnosis and genetic counseling of deciduous tooth agenesis.

Cognitive, Social, and Emotional-Behavioral Outcomes in Children and Adolescents With Beckwith-Wiedemann Syndrome.

Although Beckwith-Wiedemann syndrome spectrum (BWSp) is not usually associated with intellectual disability, recent evidences calls for further investigation of cognitive development and academic skills in children with BWSp. Moreover, research has documented social difficulties and emotional-behavioral problems associated with BWSp. Nevertheless, a full characterization of socio-emotional development in BWSp is still lacking. In the current study, cognitive and socio-emotional development was assessed in 29 children with BWSp aged 5-18 years, using a test of nonverbal intelligence, a neuropsychological battery covering multiple domains, academic skills tests, and questionnaires evaluating autistic traits and emotional-behavioral problems. As expected, most participants showed adequate performance in cognitive tests. However, the findings also highlighted greater difficulties in language than visuospatial processing, strengths in social perception, as well as slowness in reading and mental calculation. The assessment of emotional-behavioral difficulties indicated a prevalent phenotype characterized by increased anxiety, low self-esteem, social withdrawal and a tendency to control externalizing reactions, but no associations with autistic traits, cognitive outcomes, and the clinical score proposed by the recent Consensus statement. Increased social perception and internalization problems likely result from coping strategies with social and care-related stress. Overall, the findings of this study inform clinical management and genetic counseling for children and adolescents with BWSp.

Abstract C125: Improving access to genetic counseling and testing for underserved populations through telehealth

Abstract Introduction: A lack of access to genetic counseling for hereditary cancer risk in rural and underserved areas is well-documented and can exacerbate disparities in cancer risk reduction and early detection. Telehealth has the potential to bridge this gap, providing remote access to specialized care. The COVID-19 pandemic accelerated telehealth availability, allowing estimation of the causal effects of shifting to a model of virtual care delivery for genetic counseling services. Methods: The Stanford Cancer Genetic Counseling Clinic provided solely in-person care at two clinical sites (Palo Alto and San Jose, CA) until March 2020, and solely virtual care from April 2020 onward. We performed a regression discontinuity design, allowing outcomes comparison before and after the threshold of early 2020, to evaluate the impact of telehealth genetic counseling on access to care for patients living in areas of higher deprivation. The assignment variable (the exposure measured before versus after the threshold) was the three-month period during which the patients were seen, with the March-May 2020 quarter excluded because of disruption of care during the early COVID-19 pandemic. The primary endpoint was proportion of patients whose primary residence zip code had a state area deprivation index of at least 4. Secondary endpoints included driving distance to the primary clinic location in Palo Alto, CA, insurance type, race/ethnicity, and primary language. Results: The study included N=5,957 patients seen in the Stanford Cancer Genetics Program between January 2017 and February 2020, and N=9,469 patients seen between June 2020 and April 2024. The regression discontinuity analysis revealed a significant discontinuity at the threshold for telehealth in access for patients living in areas of higher deprivation, who accounted for 22% of patients seen just prior to telehealth implementation and 27% just after telehealth implementation, a proportional increase of 21% (p=0.006). Mean driving distance to Palo Alto, CA also increased, from 49 minutes just prior to the threshold to 56 minutes just after (p=0.003). There were no significant differences in insurance type, race/ethnicity, or primary language across the threshold. Conclusion: The implementation of telehealth services at the Stanford Cancer Genetic Counseling Clinic significantly improved access to genetic counseling for patients from areas with higher deprivation, as evidenced by a 21% increase in the proportion of such patients among those seen. These results quantify the effectiveness of telehealth in reducing geographical and socioeconomic barriers to specialized genetic counseling and testing services. Citation Format: Jennifer L. Caswell-Jin, Hao Tang, Mina Satoyoshi, Kerry Kingham, Allison W. Kurian. Improving access to genetic counseling and testing for underserved populations through telehealth [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C125.

Clinical genetic counselors' use of people- and identity-first language in regard to patients' identification with disability.

The language surrounding disabilities has evolved from derogatory terms to the adoption of people-first language. However, identity-first language is being advocated for by some within the disability community. Using the preferred terminology is crucial to demonstrate respect and prevent stigmatization, especially in healthcare settings like genetic counseling, where language can impact relationships with the community. However, the specific language practices of genetic counselors and their underlying reasons are unclear. This qualitative study explored the language practices employed by genetic counselors when interacting with individuals with disabilities. Fifteen interviews were conducted with genetic counselors who had clinical experience. Reflexive thematic analysis revealed that the perceptions and practices about language used with patients and disability communities overall varied, with overarching themes of people-first language is the preferred and default language, counselors mirror patient language with some exceptions, acknowledging the evolving nature of language, recognizing differences in language preferences, and reacting to outdated terminology. These findings show the importance of continuing education to stay abreast of preferred verbiage within communities and individual patients.

Clinical features and genetic analysis of four children with Phelan-McDermid syndrome

To explore the clinical characteristics and genetic etiology of four children with Phelan-McDermid syndrome (PMS). Four children who had visited the Ningbo Women and Children's Hospital between June 2, 2022 and May 8, 2023 were selected as the study subjects. Clinical data of the children were collected. Genomic DNA was extracted from peripheral blood samples of the children and their parents and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing and quantitative PCR (q-PCR) analysis. All children had presented with speech and language delays and intellectual disability. Children 3 and 4 also presented with autistic behaviors. WES showed that the children 1 and 2 had respectively carried a heterozygous c.731T>C (p.Leu244Pro) and a c.2782_2851del (p.Gly928ArgfsTer4) variant of the SHANK3 gene. Sanger sequencing confirmed that their parents did not carry the same variant, suggesting that they were de novo in origin. Children 3 and 4 had respectively harbored a 121 Kb and 52.02 Kb heterozygous deletion at chromosome 22q13.33, which had both encompassed the SHANK3 and ACR genes mapped to 22q13.33. q-PCR results showed that the deletion of SHANK3 and ACR genes were de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.731T>C and c.2782_2851del variants were predicted to be likely pathogenic (PS2+PM2_Supporting+PP3) and pathogenic (PVS1+PM2_Supporting+PS2_Supporting), respectively. Furthermore, the 52.02 Kb and 121 Kb heterozygous deletions in 22q13.33 were both predicted to be pathogenic (2D+4C, 1.05 in score; 2D+4C, 1 in score). The four children were all diagnosed with PMS by genetic testing. Above finding has enriched the phenotypic and mutational spectrum of PMS, and provided a basis for clinical diagnosis and genetic counseling for their families.

Novel PTPRQ variants associated with hearing loss in a Chinese family PTPRQ variants in Chinese hearing loss.

Hearing loss is one of the most prevalent congenital sensory disorders. Over 50% of congenital hearing loss cases are attributed to genetic factors. The PTPRQ gene encodes the protein tyrosine phosphatase receptor Q, which plays an important role in maintaining the structure and function of the stereocilia of hair cells. Variants in the PTPRQ gene have been implicated in hereditary sensorineural hearing loss. Utilizing next-generation sequencing technology, we identified novel compound heterozygous variants (c.977G>A:p.W326X and c.6742C>T:p.Q2248X) in the PTPRQ gene within a Chinese national lineage, marking the first association of these variants with hereditary sensorineural hearing loss. Our findings further emphasize the critical role of PTPRQ in auditory function and contribute to a more comprehensive understanding of PTPRQ-associated hearing loss mechanisms, aiding in clinical management and genetic counseling.

Report of a child with Bainbridge-Ropers syndrome due to a novel variant of ASXL3 gene and a literature review

To explore the clinical phenotype and genetic basis of a child with Bainbridge-Ropers syndrome (BRPS). A child with BRPS who had visited Nanjing Children's Hospital on June 26, 2019 was selected as the study subject. Clinical data of the child was reviewed. Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The child was a 6-month-old girl with peculiar facial features, feeding difficulties, malnutrition, global developmental delay, hypotonia, mildly elevated aminotransferase and ulnar deviation. Results of WES showed that she has harbored a c.1533_1534del variant of the ASXL3 gene. Sanger sequencing confirmed that neither of her parents has carried the same variant. No similar case had been retrieved from the HGMD and ClinVar databases. No frequency for this variant among Asian populations was available in the ExAC, 1000 Genomes, and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1533_1534del variant of the ASXL3 gene was determined to be likely pathogenic (PVS1+PS2+PM2_Supporting). The ASXL3 gene c.1533_1534del variant probably underlay the BRPS in this child. Above finding has provided a reference for the clinical diagnosis and genetic counseling for children with similar disorders.

How exome sequencing improves the diagnostics and management of men with non-syndromic infertility.

Male infertility affects approximately 17% of all men and represents a complex disorder in which not only semen parameters such as sperm motility, morphology, and number of sperm are highly variable, but also testicular phenotypes range from normal spermatogenesis to complete absence of germ cells. Genetic factors significantly contribute to the disease but chromosomal aberrations, mostly Klinefelter syndrome, and microdeletions of the Y-chromosome have remained the only diagnostically and clinically considered genetic causes. Monogenic causes remain understudied and, thus, often unidentified, leaving the majority of the male factor couple infertility pathomechanistically unexplained. This has been changing mostly because of the introduction of exome sequencing that allows the analysis of multiple genes in large patient cohorts. As a result, pathogenic variants in single genes have been associated with non-syndromic forms of all aetiologic sub-categories in the last decade. This review highlights the contribution of exome sequencing to the identification of novel disease genes for isolated (non-syndromic) male infertility by presenting the results of a comprehensive literature search. Both, reduced sperm count in azoospermic and oligozoospermic patients, and impaired sperm motility and/or morphology, in asthenozoospermic and/or teratozoospermic patients are highly heterogeneous diseases with well over 100 different candidate genes described for each entity. Applying the standardized evaluation criteria of the ClinGen gene curation working group, 70 genes with at least moderate evidence to contribute to the disease are highlighted. The implementation of these valid disease genes in clinical exome sequencing is important to increase the diagnostic yield in male infertility and, thus, improve clinical decision-making and appropriate genetic counseling. Future advances in androgenetics will continue to depend on large-scale exome and genome sequencing studies of comprehensive international patient cohorts, which are the most promising approaches to identify additional disease genes and provide reliable data on the gene-disease relationship.

Genetic Testing of Patients with Inherited Retinal Diseases in the European Countries: An International Survey by the European Vision Institute.

The purpose of this project was to explore the current standards of clinical care genetic testing and counseling for patients with inherited retinal diseases (IRDs) from the perspective of leading experts in selected European countries. Also, to gather opinions on current bottlenecks and future solutions to improve patient care. On the initiative of the European Vision Institute, a survey questionnaire with 41 questions was designed and sent to experts in the field from ten European countries. Each participant was asked to answer with reference to the situation in their own country. Sixteen questionnaires were collected by November 2023. IRD genetic tests are performed in clinical care settings for 80% or more of tested patients in 9 countries, and the costs of genetic tests in clinical care are covered by the public health service to the extent of 90% or more in 8 countries. The median proportion of patients who are genetically tested, the median rate of genetically solved patients among those who are tested, and the median proportion of patients receiving counseling are 51-70%, 61-80%, and 61-80%, respectively. Improving the education of healthcare professionals who facilitate patient referrals to specialized centers, improving access of patients to more thorough genotyping, and increasing the number of available counselors were the most advocated solutions. There is a significant proportion of IRD patients who are not genetically tested, whose genetic testing is inconclusive, or who do not receive counseling. Educational programs, greater availability of state-of-the-art genotyping and genetic counselors could improve healthcare for IRD patients.

Clinical and genetic features in autosomal recessive bestrophinopathy in Chinese cohort

PurposeTo provide a genotype and phenotype characterization of the BEST1 mutation in Chinese patients with autosomal recessive bestrophinopathy (ARB) through multimodal imaging and next-generation sequencing (NGS).MethodsSeventeen patients from 17 unrelated families of Chinese origin with ARB were included in a retrospective cohort study. Phenotypic characteristics, including anterior segment features, were assessed by multimodal imaging. Multigene panel testing, involving 586 ophthalmic disease-associated genes, and Sanger sequencing were performed to identify disease-causing variants.ResultsAmong 17 ARB patients, the mean follow-up was 15.65 months and average onset age was 30.53 years (range: 9–68). Best corrected visual acuity ranged from light perception to 0.8. EOG recordings showed a typically decreased Arden ratio in 12 patients, and a normal or slightly decreased Arden ratio in two patients. Anterior features included shallow anterior chambers (16/17), ciliary pronation (16/17), iris bombe (13/17), iridoschisis (2/17), iris plateau (1/17), narrow angles (16/17) and reduced axial lengths (16/17). Sixteen patients had multiple bilateral small, round, yellow vitelliform deposits distributed throughout the posterior pole, surrounding the optic disc. Initial diagnoses included angle-closure glaucoma (four patients), Best disease (three patients), and central serous chorioretinopathy secondary to choroidal neovascularization (CNV) (one patient), with the remainder diagnosed with ARB. Fourteen patients underwent preventive laser peripheral iridotomy, four of whom also received combined trabeculectomy and iridotomy in both eyes for uncontrolled intraocular pressure. One patient received intravitreal conbercept for CNV. Overall, 15 distinct disease-causing variants of BEST1 were identified, with 14 (82.35%) patients having missense mutations. Common mutations included p. Arg255-256 and p. Ala195Val (both 23.68%), with the most frequent sites in exons 7 and 5.ConclusionsThis study provides a comprehensive characterization of anterior segment and genetic features in ARB, with a wide array of morphological abnormalities. Findings are relevant for refining clinical practices and genetic counseling and advancing pathogenesis research.

Clinical phenotypic and genetic analysis of syndrome families with EYA1 gene variants

Objective:To investigate the clinical phenotype of a family with branchio-oto syndrome （BOS） and to explore the genetic etiology of the syndrome in this family. Methods:Clinical data were collected from a child diagnosed with BOS and his family members. Genomic DNA was extracted from peripheral blood of the proband and his family members. Whole-exome sequencing was performed, and the mutation sites were verified and analyzed by Sanger sequencing. Results:The family consists of two generations with four members, three of whom exhibit the phenotype. Two members have hearing loss and bilateral preauricular fistulas and bilateral branchial cleft fistulas. One member has bilateral preauricular fistulas and bilateral branchial cleft fistulas. All of which were in line with the clinical diagnosis of gill ear syndrome, the inheritance mode of the family was autosomal dominant inheritance, genetic testing showed that all members of the family had c. 1744delC（p. L592Cfs*47） mutation in the EYA1 gene, while unaffected members have the wild-type allele at this locus. This mutation is a frameshift mutation, which results in the early appearance of the stop codon, and has not been reported so far. According to ACMG guidelines, the variant was preliminarily determined to be suspected pathogenic. Conclusion:The newly discovered EYA1c. 1744delC（p. L592Cfs*47） mutation in this family is the pathogenic mutant gene of the patients in this family, which further expands the mutation spectrum of EYA1 gene, gives us a new understanding of the disease, and provides an important reference for clinical diagnosis and genetic counseling.

Coinherited Hemoglobin Lansing-Ramathibodi/Southeast Asian Deletional α0-thalassemia and Hemoglobin E Causing Falsely Low Oxygen Saturation on Pulse Oximetry

OBJECTIVE Hemoglobin (Hb) variants resulting from mutations in globin genes and leading to qualitative abnormalities of globin proteins can result in a spectrum of clinical presentations. Herein we describe a case of a 10-year-old boy with an Hb variant, Hb Lansing-Ramathibodi (HBA1:c.264C>G, codon 87 His>Gln), who was incidentally found to have low pulse oximetry oxygen saturation readings (low SpO2). Laboratory investigations revealed mild microcytic anemia. Arterial blood gas showed normal partial pressure of oxygen (PaO2) and arterial oxygen saturation (SpO2) values, indicating an oxygen saturation gap. Subsequent Hb analysis identified an abnormal peak, prompting further molecular studies which confirmed the coinheritance of Hb Lansing-Ramathibodi, Southeast Asian deletional α0-thalassemia and the Hb E trait. The patient’s mother, carrying the Hb Lansing-Ramathibodi and Hb E traits without Southeast Asian deletional α 0-thalassemia, was asymptomatic. This case underscores the importance of identifying and characterizing rare Hb variants presenting with an oxygen saturation gap for informed clinical management and genetic counseling. KEYWORDS alpha-thalassemia, coinheritance, hemoglobin Lansing- Ramathibodi, low SpO2, oxygen saturation

Performance analysis of non-invasive prenatal testing for trisomy 13, 18, and 21: A large-scale retrospective study (2018–2021)

BackgroundNon-invasive prenatal tests (NIPT) are used to screen for trisomy 21, 18, and 13. This study investigated NIPT performance and the clinical significance of its results. MethodsPregnant women (n = 282,911) participating in a free NIPT (April 2018–December 2021) were screened for common trisomies, and the results were retrospectively analyzed. NIPT performance was evaluated by its positive predictive value (PPV), sensitivity, and specificity. Results were analyzed using number, percentage, and chi-squared/t-test analyses. ResultsAfter NIPT screening, patients with common trisomies (n = 746) included 457 with T21, 160 with T18, and 129 with T13. Seven false negative cases were identified. High PPV (86.81 %, 56.81 %, 18.18 %), sensitivity (99.25 %, 98.33 %, 100.00 %), and specificity (99.98 %, 99.98 %, 99.97 %) values were detected for trisomy 21, 18, and 13, respectively. The PPVs of common trisomies were significantly different between pregnant women older than 35 (85.53 %, 136/159) and those aged 35 or younger (58.90 %, 311/528) (χ2 = 125.02, P = 2.20e-16). As the NIPT uptake increased from 2018 to 2021, live-born birth defect incidence decreased. ConclusionNIPT performed well in screening for T21, T18, and T13. Our discoveries offer an important and useful guideline in laboratory and clinical genetic counseling.

Expert consensus on clinical genetic counseling of α-thalassemia gene analysis

α-thalassemia is a type of microcytic hypochromic anemia caused by variants of alpha-globin gene, and is one of the most common monogenic disorders in southern China. The population screening model based on hematologic phenotype has achieved great results in areas with high incidence of thalassemia. However, with the continuous decline of the cost of genetic testing and implementation of screening programs for thalassemia gene carriers, more variants in the alpha-globin gene have been discovered, which also brings great challenges to clinical genetic counseling. From the perspective of alpha-globin genetic analysis, this consensus has discussed the contents of pre- and post-test genetic counseling, with an aim to provide standardized guidance for clinicians.

Clinical and genetic analysis of a child with X-linked mental retardation due to variant of SLC9A7 gene

To explore the clinical and genetic characteristics of a child with mental retardation, language and motor developmental delay and epilepsy. A child who was admitted to the First Affiliated Hospital of Zhengzhou University in March 2020 for intermittent seizures for over two months was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his parents were collected and subjected to high throughput sequencing. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. The clinical manifestations of the child have included mental retardation, language and motor developmental delay, and seizures. High-throughput sequencing revealed that he has harbored a hemizygous splice site variant (NM_032591.3: c.1030-1G>C) of the SLC9A7 gene, which was inherited from his mother and unreported previously. The hemizygous splice site variant (NM_032591.3: c.1030-1G>C) of the SLC9A7 gene probably underlay the disease in this child. Above finding has provided a basis for clinical diagnosis and genetic counseling.

Deciphering potential causative factors for undiagnosed Waardenburg syndrome through multi-data integration

BackgroundWaardenburg syndrome (WS) is a rare genetic disorder mainly characterized by hearing loss and pigmentary abnormalities. Currently, seven causative genes have been identified for WS, but clinical genetic testing results show that 38.9% of WS patients remain molecularly unexplained. In this study, we performed multi-data integration analysis through protein-protein interaction and phenotype-similarity to comprehensively decipher the potential causative factors of undiagnosed WS. In addition, we explored the association between genotypes and phenotypes in WS with the manually collected 443 cases from published literature.ResultsWe predicted two possible WS pathogenic genes (KIT, CHD7) through multi-data integration analysis, which were further supported by gene expression profiles in single cells and phenotypes in gene knockout mouse. We also predicted twenty, seven, and five potential WS pathogenic variations in gene PAX3, MITF, and SOX10, respectively. Genotype-phenotype association analysis showed that white forelock and telecanthus were dominantly present in patients with PAX3 variants; skin freckles and premature graying of hair were more frequently observed in cases with MITF variants; while aganglionic megacolon and constipation occurred more often in those with SOX10 variants. Patients with variations of PAX3 and MITF were more likely to have synophrys and broad nasal root. Iris pigmentary abnormality was more common in patients with variations of PAX3 and SOX10. Moreover, we found that patients with variants of SOX10 had a higher risk of suffering from auditory system diseases and nervous system diseases, which were closely associated with the high expression abundance of SOX10 in ear tissues and brain tissues.ConclusionsOur study provides new insights into the potential causative factors of WS and an alternative way to explore clinically undiagnosed cases, which will promote clinical diagnosis and genetic counseling. However, the two potential disease-causing genes (KIT, CHD7) and 32 potential pathogenic variants (PAX3: 20, MITF: 7, SOX10: 5) predicted by multi-data integration in this study are all computational predictions and need to be further verified through experiments in follow-up research.