Inherited conditions have implications not only for the individual affected but for the entire family. It is in this context that family communication of genetic risk information is important to understand. This paper aims to provide an overview of the construct of family communication of genetic risk and provide implications for healthcare providers. A search of relevant literature was done with electronic databases including PubMed, CINAHL, Embase, Scopus, and Web of Science. The findings from the literature were organized based on the Family Communication of Genetic Risk (FCGR) conceptual framework which highlights the attributes of the family communication of genetic risk process including influential factors, communication strategy, communication occurrence, and outcomes of communication. Healthcare providers need to understand how individuals share genetic risk with their family members so that appropriate support and interventions can be provided to them. This is especially important across countries, including the Philippines, as genetic services and testing move beyond the traditional medical genetics clinic to other medical specialties, a development where we would expect an increase in individuals and family members undergoing genetic evaluation and testing.

Inherited conditions have implications not only for the individual affected but for the entire family. It is in this context that family communication of genetic risk information is important to understand. This paper aims to provide an overview of the construct of family communication of genetic risk and provide implications for healthcare providers. A search of relevant literature was done with electronic databases including PubMed, CINAHL, Embase, Scopus, and Web of Science. The findings from the literature were organized based on the Family Communication of Genetic Risk (FCGR) conceptual framework which highlights the attributes of the family communication of genetic risk process including influential factors, communication strategy, communication occurrence, and outcomes of communication. Healthcare providers need to understand how individuals share genetic risk with their family members so that appropriate support and interventions can be provided to them. This is especially important across countries, including the Philippines, as genetic services and testing move beyond the traditional medical genetics clinic to other medical specialties, a development where we would expect an increase in individuals and family members undergoing genetic evaluation and testing.
communication ; family ; genetic predisposition to disease ; genetic testing

ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020, a supplementary practical guidelines, is based on the Standards and Guidelines for the Interpretation of Sequence Variations issued by the American Society for Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP) in 2015 by the British Medical Genetics Society under the Clinical Genomics Society (ACGS), and has integrated the detailed rules of standards developed by the ClinGen Sequence Variant Interpretation (SVI) Working Group by 2020. The further development of the ACMG/AMP guidelines is currently undertaken by the ClinGen SVI working group in the United States, which focuses on the classification of high penetrance and protein coding variants. ClinGen has established many expert panels on variants for specific diseases which required various evidence thresholds and is currently developing disease/gene specific guidelines. The British Medical Genetics Society has collected and integrated information on the guidelines for sequence variation classification and their extended rules, forming its own "2020 ACGS Best Practice Guidelines for Rare Disease Variation Classification" and is regularly updating it. The author has translated and summarized it for the reference of Chinese Medical Genetics Practitioners.
Humans ; Genetic Testing ; Genetic Variation ; Genome, Human ; Rare Diseases/genetics* ; China

OBJECTIVE: To explore the genetic basis of a Chinese pedigree affected with chronic kidney disease (CKD). METHODS: A Chinese pedigree comprised of 10 individuals from four generation who had visited the First Affiliated Hospital of Dali University from August 15, 2018 to July 5, 2021 was selected as the study subject. Clinical data of the proband were collected, and a pedigree survey was conducted. The proband was subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The proband, a 41-year-old female, has been diagnosed with chronic nephritis for more than 4 years. Routine urinary examination showed proteinuria and blood creatinine of 1 130 μmol/L. Renal biopsy has revealed hyperplastic glomerulonephritis, moderate tubulointerstitial disease and renal arteriosclerosis. Her elder sister, younger brother, younger sister and mother were all diagnosed with CKD stage 5. Except for her elder sister, all of them had deceased, whilst no abnormality was found in the remainders. Genetic testing revealed that the proband and four family members had harbored a c.467G>A missense variant of the PAX2 gene. The variant has been associated with focal segmental glomerulosclerosis and classified as likely pathogenic (PS1+PP3+PP4) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). CONCLUSION The c.167G＞A variant of the PAX2 gene probably underlay the CKD in this Chinese pedigree.
Adult ; Female ; Humans ; Male ; East Asian People ; Genetic Testing ; Mutation ; PAX2 Transcription Factor/genetics* ; Pedigree ; Renal Insufficiency, Chronic/genetics*

OBJECTIVE: To analyze the clinical and genetic characteristics of an infant with craniosynostosis. METHODS: An infant who was admitted to Wuhan Children's Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology in April 2021 due to widening of the lateral ventricles for over a month was selected as the study subject. Clinical data of the patient was collected. Peripheral blood samples were collected from the infant and her parents for chromosomal karyotyping and whole exome sequencing. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. Relevant literature was retrieved from the PubMed, Wanfang and CNKI databases (up to December 2021) by using key words including ERF gene, craniosynostosis, ERF mutation, craniosynostosis and ERF-related craniosynostosis. RESULTS: The infant, a 1-month-and-16-day-old female, was found to have sagittal synostosis by cranial X-ray radiography. Genetic testing revealed that she has harbored a heterozygous c.787C>T (p.Q263*) variant of the ERF gene, which was not found in either parent. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted as pathogenic (PVS1+PS2+PM2_Supporting). In total 63 relevant cases were retrieved from the database, and a total of 64 individuals were analyzed by genetic testing. Most of the cases were sporadic and males. Multiple cranial sutures (including at least two of the sagittal suture, coronal suture, lambdoid suture, and frontal suture) were involved in 45.45% of the cases, and those with sagittal suture closure only have accounted for 20.00%. The main clinical manifestations have included hypertelorism, exophthalmos, development delay, malar dysplasia, etc. Chiari type 1 malformation may present in some patients. Variants of the ERF gene have mainly included splicing and deletional variants, and there was a strong genetic heterogeneity among the infants and their pedigrees. CONCLUSION The c.787C>T (p.Q263*) variant of the ERF gene probably underlay the craniosynostosis of this infant. Above finding has enriched the phenotype ~ genotype spectrum of the ERF gene.
Female ; Humans ; Cranial Sutures/surgery* ; Craniosynostoses/genetics* ; Genetic Testing ; Mutation ; Repressor Proteins/genetics* ; Infant

OBJECTIVE: To compare the prevalence of chromosomal aneuploidies and pregnancy outcomes of D5 and D6 blastocysts subjected to preimplantation genetic testing for aneuploidy (PGT-A). METHODS: Clinical and laboratory data of 268 couples who underwent PGT-A at the Reproductive Center of the First Affiliated Hospital of Zhengzhou University from September 2018 to September 2020 were collected. The prevalence of chromosomal aneuploidies and pregnancy outcomes of D5/D6 biopsied blastocysts were compared. RESULTS: Compared with D6 blastocysts, the euploidy rate of D5 blastocysts was significantly higher (49.1% vs. 41.1%, P = 0.001 1), whilst their aneuploidy rate was significantly lower (50.9% vs. 58.9%, P = 0.001 1). The rate of numerical abnormalities of D6 blastocysts was significantly higher than that of D5 blastocysts (27.9% vs. 20.2%, P = 0.000 5). For patients under 35 years old, the euploidy rate of D5 blastocysts was significantly higher than that of D6 blastocysts (53.8% vs. 44.3%, P = 0.001), whilst the numerical abnormality rate was significantly lower (16.3% vs. 23.9%, P = 0.001). For both D5 and D6 blastocysts, the euploidy rates for patients <= 35 were significantly higher than those for > 35. The elder group had the lowest rates for aneuploidies and live births. Compared with those receiving D6 blastocysts transplantation, the pregnancy rate, implantation rate and live birth rate for those receiving thawed D5 blastocysts transplantation were significantly higher (60.2% vs.37.0%, P = 0.000 3; 59.1% vs.37.0%, P = 0.000 6; 47.7% vs. 28.3%, P = 0.002). CONCLUSION For patients undergoing PGT-A, the chromosomal euploidy rate for D5 blastocysts is higher than that for D6 blastocysts, and the clinical outcome of D5 blastocysts with normal signal is better than that of D6 blastocysts. Elder patients have a higher rate of aneuploidies.
Female ; Pregnancy ; Humans ; Aged ; Adult ; Pregnancy Outcome ; Aneuploidy ; Blastocyst ; Genetic Testing ; Laboratories

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a patient with Alport syndrome. METHODS: A patient with Alport syndrome who had visited the First Affiliated Hospital of Zhengzhou University in November 2020 was selected as the study subject. Clinical data of the patient were collected. High-throughput sequencing was carried out to detect potential variant of the COL4A3, COL4A4 and COL4A5 genes, and Sanger sequencing was carried out for verification of candidate variants in the family. RESULTS: The main clinical manifestations of the patient included hematuria, proteinuria, and impaired hearing. Audiometric testing suggested symmetrical cochlear sensory neural hearing loss on both sides. Renal biopsy revealed mild mesangial proliferative glomerulonephritis. Genetic testing revealed that the patient has harbored compound heterozygous variants of the COL4A4 gene, namely c.940G>A (p.Gly314Ser) and c.3773G>A (p.Gly1258Asp), which were respectively inherited from her father and mother. Neither variant has been reported before, and were predicted to be pathogenic based on the guidelines from the American College of Medical Genetics and Genomics. CONCLUSION The c.940G>A (p.Gly314Ser) and c.3773G>A (p.Gly1258Asp) compound heterozygous variants of the COL4A4 gene probably underlay the Alport syndrome in this patient. Above finding has enriched the mutational spectrum of the COL4A4 gene.
Female ; Humans ; Nephritis, Hereditary/genetics* ; Hematuria ; Genetic Testing ; Genomics ; Hearing ; Collagen Type IV/genetics*

OBJECTIVE: To explore the clinical and genetic characteristics of a child with Arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: A 6-year-old boy with ARVC who had visited Fujian Provincial Children's Hospital on August 23, 2022 was selected as the study subject. Relevant clinical data were collected, and peripheral venous blood samples were collected from the child and his parents for genetic testing through whole exome sequencing (WES). Sanger sequencing was carried out for family verification, and pathogenicity analysis was conducted for the candidate variants. RESULTS: The child had exhibited clinical symptoms including systemic edema, generalized heart enlargement, universal reduction of interventricular septum and ventricular wall movement, reduced left ventricular diastolic and systolic function, and reduced right ventricular systolic function. WES revealed that the child has harbored compound heterozygous variants of the PKP2 gene, namely c.119_122del (p.Leu40ArgfsTer71) and c.1978G>A (p.Gly660Arg), which were verified by Sanger sequencing to be respectively inherited from his father and mother. The c.119_122del variant has not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to lead to truncation of the PKP2 protein by SWISS-MODEL and PyMOL online software and classified as likely pathogenic based on the guidelines jointly developed by the American College of Medical Genetics and Genomics (ACMG) and ClinGen. The c.1978G>A variant has also not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to be deleterious by online software including REVEL, SIFT, CADD, Mutation Taster, and PolyPhen-2. The amino acid encoded by the variant site was highly conserved among various species by analysis using T-coffee and ESPript v3.0 online servers. The variant may affect the protein function by SWISS-MODEL and PyMOL online server analysis, and was classified as likely pathogenic based on the guidelines jointly developed by the ACMG and ClinGen. CONCLUSION The compound heterozygous variants of c.119_122del (p.Leu40ArgfsTer71) and c.1978G>A (p.Gly660Arg) of the PKP2 gene probably underlay the ARVC in this child. Above finding has broadened the spectrum of PKP2 gene variants and provided a reference for the diagnosis and genetic counseling.
Male ; Child ; Humans ; Arrhythmogenic Right Ventricular Dysplasia/genetics* ; Diastole ; Ethnicity ; Genetic Counseling ; Genetic Testing ; Plakophilins/genetics*

OBJECTIVE: To explore the clinical and genetic characteristics of eight children with Primary hypertrophic cardiomyopathy (HCM). METHODS: Eight children with HCM admitted to the Department of Cardiology of Henan Children's Hospital from January 2018 to December 2021 were selected as the study subjects. Clinical data of the children were collected. Whole exome sequencing was carried out on two children, and trio whole exome sequencing was carried out on the remainder 6 children. Sanger sequencing was used to verify the candidate variants in the children and their parents, and the pathogenicity of the variants was evaluated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The patients had included 5 males and 3 females, with their ages ranging from 5 to 13 years old. The average age of diagnosis was (7.87 ± 4.8) years old, and the cardiac phenotype showed non-obstructive HCM in all of the patients. WES has identified variants of the MYH7 gene in 4 children, including c.2155C>T (p.Arg719Trp), c.1208G>A (p.Arg403Gln), c.1358G>A (p.Arg453His), and c.1498G>A (p.Glu500Lys). Based on the guidelines from the ACMG, the first 3 variants were classified as pathogenic, while c.1498G>A (p.Glu500Lys) was classified as likely pathogenic (PM1+PM2_Supporting+PM6+PP3), which was also unreported previously. The remaining four children had all harbored maternal variants, including MYL2: c.173G>A (p.Arg58Gln; classified as pathogenic), TPM1: c.574G>A (p.Glu192Lys) and ACTC1: c.301G>A (p.Glu101Lys)(both were classified as likely pathogenic), and MYBPC3: c.146T>G (p.Ile49Ser; classified as variant of uncertain significance). Seven children were treated with 0.5 ~ 3 mg/(kg·d) propranolol, and their symptoms had improved significantly. They were followed up until September 30, 2022 without further cardiac event. CONCLUSION Genetic testing can clarify the molecular basis for unexplained cardiomyopathy and provide a basis for clinical diagnosis and genetic counseling. Discovery of the c.1498G>A (p.Glu500Lys) variant has also expanded the spectrum of MYH7 gene mutations underlying HCM.
Female ; Male ; Humans ; Child ; Child, Preschool ; Adolescent ; Cytoskeletal Proteins ; Family ; Genetic Counseling ; Genetic Testing ; Cardiomyopathy, Hypertrophic/genetics*

OBJECTIVE: To explore the correlation between clinical manifestations of Limb-girdle muscular dystrophy autosomal recessive 9 FKRP-related (R9 FKRP-related) and variants of the FKRP gene. METHODS: Two children who had presented at the Children's Hospital of Nanjing Medical University respectively due to increased serum myocardial zymogram and hepatic dysfunction on September 30, 2018 and August 3, 2018 were selected as the study subjects. Clinical data of the children were collected. Both children were suspected for Duchenne or Becker muscular dystrophy for asymptomatic high creatine kinase (CK) levels. Peripheral blood samples of the children and their parents were collected for whole exome sequencing, and candidate variants were validated by Sanger sequencing. RESULTS: Genetic testing revealed that both children have carried compound heterozygous variants of the FKRP gene. The c.545A>G and c.941C>T variants in child 1 have been reported previously, among which the c.545A>G is a hot spot mutation in the Chinese population. Child 2 has carried c.602T>C and c.961G>A variants, both of which were unreported previously. CONCLUSION Both children have met the diagnostic criteria for LGMD R9 FKRP-related. Carriers of the c.545A>G variant may present milder symptoms. Compared with patients carrying null variants, carriers of compound heterozygous missense variants may present with a milder phenotype, manifesting as asymptomatic high CK level.
Humans ; Child ; Asian People/genetics* ; Genetic Testing ; Muscular Dystrophies, Limb-Girdle/genetics* ; Muscular Dystrophy, Duchenne ; Pentosyltransferases/genetics*