Diagnóstico prenatal de clorhidrorrea congénita: reporte de caso / Prenatal diagnosis of congenital chloride diarrhea: A case report

La clorhidrorrea congénita es un trastorno genético infrecuente pero importante caracterizado por una alteración grave del balance hidroelectrolítico como resultado de un defecto en la absorción intestinal de cloruros. Los niños afectados presentan diarrea persistente, deshidratación y malnutrición; el control médico y del desarrollo son complejos. Mejorar la detección prenatal es esencial para facilitar la atención del paciente, las intervenciones tempranas y el asesoramiento genético informado. Sin embargo, a pesar de los avances de la medicina, la naturaleza compleja y la escasa frecuencia de esta entidad, constituyen un desafío para la detección prenatal. En este estudio, se reporta el caso de una embarazada donde los estudios por imágenes de resonancia magnética fetales identificaron en forma efectiva las características típicas de la clorhidrorrea congénita. Se proveen conocimientos sobre las complejidades del diagnóstico y se sugieren caminos para las estrategias de detección temprana de esta enfermedad.

Congenital chloride diarrhea (CCD) is a rare but significant genetic disorder characterized by severe electrolyte imbalances resulting from impaired intestinal chloride absorption. Affected children experience persistent diarrhea, dehydration, and malnutrition, complicating medical and developmental care. The enhancement of prenatal detection is crucial for improved patient management, early interventions, and informed genetic counseling. However, despite advancements in medicine, the complex nature and rarity of CCD make prenatal detection challenging. In this study, we report a fetal case where prenatal magnetic resonance imaging (MRI) effectively identified the distinctive characteristics of CCD, providing insights into the complexities of diagnosis and suggesting avenues for enhanced early detection strategies.

Clinical phenotype and genetic analysis of a fetus with Cardiac valvular dysplasia type 1 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with Cardiac valvular dysplasia type 1 (CVDP1).@*METHODS@#A CVDP1 fetus identified at the Ningbo Women and Children's Hospital on July 7, 2022 was selected as the study subject. Clinical data of the fetus was collected. The fetus and its parents were subjected to trio-whole exome sequencing (trio-WES), and candidate variants were verified by Sanger sequencing.@*RESULTS@#The fetus had exhibited generalized edema, complex cardiac malformation, abdominal effusion, and enhanced intestinal and renal parenchymal echoes. Trio-WES revealed that it has harbored compound heterozygous variants of the PLD1 gene, namely c.2977C>T (p.R993*) and c.1460G>A (p.W487*), which were respectively inherited from its father and mother. Neither variant was reported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2977C>T (p.R993*) variant was evaluated to be likely pathogenic (PVS1_Moderate+PM2_Supporting+PM3+PP4), whilst the c.1460G>A (p.W487*) variant was evaluated to be pathogenic (PVS1+PM2_Supporting+PP4).@*CONCLUSION@#The c.2977C>T (p.R993*) and c.1460G>A (p.W487*) compound heterozygous variants of the PLD1 gene probably underlay the CVDP1 in the fetus. Above discovery has enriched the mutational spectrum of the PLD1 gene and provided a guidance for genetic counseling and prenatal diagnosis in this family.

Clinical characteristics and genetic counseling for a three-generation Chinese pedigree with recurrent fetal Kabuki syndrome due to variant of KDM6A gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a pregnant woman with a history of adverse pregnancy outcomes.@*METHODS@#A woman with an adverse history of pregnancies including one fetal demise and two induced abortions due to fetal diaphragmatic hernia and complex cardiac anomalies was selected as the study subject. Muscle tissue from the induced abortus was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing of the couple and other family members.@*RESULTS@#Genetic sequencing revealed that the fetus has harbored a frameshift variant of the KDM6A gene (NM_001291415.2), namely c.1228_1229del (p.Gln410GlufsTer2), which was inherited from the woman and her mother. The variant was unreported previously, and the woman was found to have short stature, sparse eyebrows in the outer third, peculiar facial features, but normal intelligence in addition with female congenital genital malformation, like incomplete vaginal septum, double cervix, double uterus, and unilateral ovary absence. mostly similar phenotypes observed in her mother.@*CONCLUSION@#The hemizygous c.1228_1229del variant of the KDM6A gene probably underlay the abnormalities in the fetus. All findings have enabled genetic counseling for this family featuring X-linked inheritance, and the woman had given birth to a healthy girl with appropriate prevention and intervention.

Research progress on hereditary endocrine and metabolic diseases associated with sensorineural hearing loss / 临床耳鼻咽喉头颈外科杂志

Hereditary endocrine and metabolic diseases , caused by genetic factors, exhibit complex and diverse symptoms, including the possibility of concurrent sensorineural deafness. Currently, there is a limited clinical understanding of hereditary endocrine and metabolic diseases that manifest with deafness, the pathogenesis remains unclear,and there is a lack of effective diagnostic and treatment methods. This article summarizes the research progress of hereditary endocrine and metabolic diseases complicated with deafness from the pathogenesis, clinical phenotype, diagnosis and treatment. Understanding the current research progress and integrating genetic analysis into clinical practice are crucial for accurate diagnosis and treatment, evaluating clinical efficacy, and providing effective genetic counseling for these diseases.

Genetic counseling for hearing loss today / 临床耳鼻咽喉头颈外科杂志

Genetic counseling for hearing loss today originated from decoding the genetic code of hereditary hearing loss, which serves as an effective strategy for preventing hearing loss and constitutes a crucial component of the diagnostic and therapeutic framework. This paper described the main principles and contents of genetic counseling for hearing loss, the key points of counseling across various genetic models and its application in tertiary prevention strategies targeting hearing impairment. The prospects of an AI-assisted genetic counseling decision system and the envisions of genetic counseling in preventing hereditary hearing loss were introduced. Genetic counseling for hearing loss today embodies the hallmark of a new era, which is inseparable from the advancements in science and technology, and will undoubtedly contribute to precise gene intervention!

Germline Mutations Landscape in a Cohort of the State of Minas Gerais, Brazil, in Patients Who Underwent Genetic Counseling for Gynecological and Breast Cancer / Cenário de mutações germinativas em uma coorte do estado de Minas Gerais, Brasil, em pacientes submetidas ao aconselhamento genético para câncer ginecológico e de mama

Abstract Objective The present study evaluated the profile of germline mutations present in patients who underwent genetic counseling for risk assessment for breast cancer (BC), ovarian cancer (OC), and endometrial cancer (EC) with a possible hereditary pattern. Methods Medical records of 382 patients who underwent genetic counseling after signing an informed consent form were analyzed. A total of 55.76% of patients (213/382) were symptomatic (personal history of cancer), and 44.24% (169/382) were asymptomatic (absence of the disease). The variables analyzed were age, sex, place of birth, personal or family history of BC, OC, EC, as well as other types of cancer associated with hereditary syndromes. The Human Genome Variation Society (HGVS) nomenclature guidelines were used to name the variants, and their biological significance was determined by comparing 11 databases. Results We identified 53 distinct mutations: 29 pathogenic variants, 13 variants of undetermined significance (VUS), and 11 benign. The most frequent mutations were BRCA1 c.470_471delCT, BRCA1 c.4675 + 1G > T, and BRCA2 c.2T> G. Furthermore, 21 variants appear to have been described for the first time in Brazil. In addition to BRCA1/2 mutations, variants in other genes related to hereditary syndromes that predispose to gynecological cancers were found. Conclusion This study allowed a deeper understanding of the main mutations identified in families in the state of Minas Gerais and demonstrates the need to assess the family history of non-gynecological cancer for risk assessment of BC, OC, and EC. Moreover, it is an effort that contributes to population studies to evaluate the cancer risk mutation profile in Brazil.

Resumo Objetivo O presente estudo avaliou o perfil de mutações germinativas presentes em pacientes submetidas a aconselhamento genético para avaliação de risco para câncer de mama (CM), câncer de ovário (OC) e câncer de endométrio (CE) com possível padrão hereditário. Métodos Foram analisados os prontuários de 382 pacientes que realizaram aconselhamento genético após consentimento informado. Um total de 55,76% dos pacientes (213/382) eram sintomáticos (história pessoal de câncer), e 44,24% (169/382) eram assintomáticos (ausência da doença). As variáveis analisadas foram idade, sexo, naturalidade, história pessoal ou familiar de CM, OC, CE bem como outros tipos de câncer associados a síndromes hereditárias. As diretrizes de nomenclatura da Human Genome Variation Society (HGVS) foram usadas para nomear as variantes e seu significado biológico foi determinado pela comparação de 11 bancos de dados. Resultados Identificamos 53 mutações distintas: 29 variantes patogênicas, 13 variantes de significado indeterminado e 11 benignas. As mutações mais frequentes foram BRCA1 c.470_471delCT, BRCA1 c.4675 + 1G > T e BRCA2 c.2T > G. Além disso, 21 variantes parecem ter sido descritas pela primeira vez no Brasil. Além das mutações BRCA1/2, foram encontradas variantes em outros genes relacionados a síndromes hereditárias que predispõem a cânceres ginecológicos. Conclusão Este estudo permitiu conhecer melhor as principais mutações identificadas nas famílias do estado de Minas Gerais e demonstra a necessidade de avaliar a história familiar de câncer não ginecológico para avaliação do risco de CM, OC e CE. Além disso, é um esforço que contribui com estudos populacionais para avaliar o perfil de mutações de risco para câncer no Brasil.

Genetic testing and clinical analysis of a patient with Dilated cardiomyopathy due to variant of FLNC gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a patient with Dilated cardiomyopathy.@*METHODS@#A patient admitted to Beijing Anzhen Hospital Affiliated to Capital Medical University in April 2022 was selected as the study subject. Clinical data and family history of the patient was collected. Targeted exome sequencing was carried out. Candidate variant was verified by Sanger sequencing and bioinformatic analysis based on guidelines of the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#DNA sequencing revealed that the patient has harbored a heterozygous c.5044dupG frameshift variant of the FLNC gene. Based on the ACMG guidelines, the variant was predicted to be likely pathogenic (PVS1+PM2_Supporting+PP4).@*CONCLUSION@#The heterozygous c.5044dupG variant of the FLNC gene probably underlay the pathogenesis in this patient, which has provided a basis for the genetic counseling for his family.

Advances in research on the clinical phenotype and genetic etiology of jaundice associated with Hereditary bilirubin metabolic disorders / 中华医学遗传学杂志

Hereditary bilirubin metabolic disorder is an important cause for jaundice. For its diverse types and similar clinical manifestations, it has been difficult to make a clear etiological diagnosis. The application of next generation sequencing in recent years has delineated the more and more genetic etiologies for jaundice. This article has reviewed the clinical manifestations and genetic etiology of bilirubin metabolic disorder jaundice, with an aim to enhance the understanding of such diseases and facilitate their clinical diagnosis and treatment, which will provide a reference for genetic counseling and/or prenatal diagnosis for the affected individuals and families.

Clinical and genetic analysis of a rare fetus with Protein C deficiency due to compound heterozygous variants of PROC gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology for a fetus with hydrocephalus and intraventricular hemorrhage.@*METHODS@#Trio whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing of the fetus and its parents.@*RESULTS@#The fetus was found to harbor c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene, which were respectively inherited from its mother and father. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PVS1_Strong+PM2_Supporting+PP4; PM2_Supporting+PM3+PP1+PP3+PP4).@*CONCLUSION@#The fetus was diagnosed with Protein C deficiency due to the c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene. Above finding has enriched the spectrum of PROC gene variants and enabled genetic counseling and prenatal diagnosis for the family.

Analysis of CLCN4 gene variant in a child with Raynaud-Claes syndrome / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and genetic variant in a child with Raynaud-Claes syndrome (RCS).@*METHODS@#A child who was diagnosed with RCS at the Children's Hospital Affiliated to Zhengzhou University for delayed language and motor development in August 2022 was selected as the study subject. Clinical data of the child were collected, and potential genetic variant was detected by next-generation sequencing and Sanger sequencing. The pathogenicity of the candidate variant was analyzed.@*RESULTS@#The child, a 4-year-and-4-month-old male, has manifested global developmental delay, speech disorders, special facial features and behavioral abnormalities. Genetic testing revealed that he has harbored a hemizygous c.1174C>T (p.Gln392Ter) variant of the CLCN4 gene, which was not detected in either of his parents. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as pathogenic (PVS1+PS2+PM2_Supporting).@*CONCLUSION@#The c.1174C>T (p.Gln392Ter) variant of the CLCN4 gene probably underlay the PCS in this child. Above finding has expanded the mutational spectrum of the CLCN4 gene and enabled genetic counseling and prenatal diagnosis for his family.

Clinical and genetic analysis of two children with Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language due to de novo variants of MEF2C gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic etiology for two children with Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (MEDHSIL).@*METHODS@#Two children who had visited the Ningbo Women and Children's Hospital on October 15, 2021 were selected as the study subjects. Whole exome sequencing (WES) was carried out for both patients. Candidate variants were verified by Sanger sequencing of their family members.@*RESULTS@#The two children were respectively found to harbor a heterozygous c.138delC (p.Ile47Serfs*42) variant and a c.833del (p.L278*) variant of the MEF2C gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS1+PS2+PM2_Supporting).@*CONCLUSION@#The c.138delC and c.833del variants of the MEF2C gene probably underlay the pathogenesis of MEDHSIL in the two children. Above findings have enriched the mutational spectrum of the MEF2C gene and enabled genetic counseling for their families.

Clinical and genetic analysis of eight children with Primary hypertrophic cardiomyopathy / 中华医学遗传学杂志

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.

Analysis of PKP2 gene variants in a child with Arrhythmogenic right ventricular cardiomyopathy / 中华医学遗传学杂志

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.

Analysis of ARX gene variant in a child with X-linked lissencephaly with abnormal genitalia / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic basis for a child with X-linked lissencephaly with abnormal genitalia (XLAG).@*METHODS@#A child with XLAG who had presented at the Third Affiliated Hospital of Zhengzhou University in May 2021 was selected as the study subject. Peripheral blood samples of the child and his parents were collected and subjected to high-throughput sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the result was analyzed by using bioinformatic software.@*RESULTS@#The child was found to have harbored a hemizygous c.945_948del variant in exon 2 of the ARX gene, which as a frameshifting variant has resulted in a truncated protein. His mother was found to be heterozygous for the variant, whilst his father was of wild type. The variant was unreported previously.@*CONCLUSION@#The hemizygous c.945_948del variant of the ARX gene probably underlay the XLAG in this patient. Above finding has provided a basis for the diagnosis and genetic counseling for this family.

Analysis of clinical characteristics and genetic variants in a child with Isolated sulfite oxidase deficiency / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with Isolated sulfite oxidase deficiency (ISOD).@*METHODS@#The child and her parents were subjected to targeted capture and next-generation sequencing. Pathogenicity of candidate variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#The child was found to harbor compound heterozygous variants of the SUOX gene, namely c.1200C>G (p.Tyr400*) and c.1406_1421delCCTGGCAGGTGGCTAA (p.Thr469Serfs*20), which were inherited from her mother and father, respectively. The c.1200C>G was a known pathogenic variant, while the c.1406_1421delCCTGGCAGGTGGCTAA was unreported previously and predicted to be a pathogenic variant (PVS1+PM2_Supporting +PM3) based on the guidelines from the American College of Medical Genetics and Genomics.@*CONCLUSION@#The compound c.1200C>G and c.1406_1421delCCTGGCAGGTGGCTAA variants of the SUOX gene probably underlay the pathogenesis of ISOD in this child. Above finding has expanded the spectrum of SUOX gene variants and provided molecular evidence for the clinical diagnosis and genetic counseling for this pedigree.

Analysis of genetic variants and clinical manifestations of two children with Kabuki syndrome / 中华医学遗传学杂志

OBJECTIVE@#To report on two children with Kabuki syndrome due to variants of the KMT2D gene and summarize their clinical and genetic characteristics.@*METHODS@#Two children who had presented at the Ningbo Women and Children's Hospital respectively on August 19 and November 10, 2021 were selected as the study subjects. Clinical data were collected. Both children were subjected to whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing.@*RESULTS@#Both children had featured motor and language developmental delay, facial dysmorphism and mental retardation. Genetic testing revealed that both had harbored de novo heterozygous variants of the KMT2D gene, namely c.10205del (p.Leu3402Argfs*3) and c.5104C>T (p.Arg1702*), both of which were rated as pathogenic variants based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*CONCLUSION@#The c.10205del (p.Leu3402Argfs*3) and c.5104C>T (p.Arg1702*) variants of the KMT2D gene probably underlay the pathogenesis in these two children. Above finding has not only provided a basis for their diagnosis and genetic counseling, but also enriched the spectrum of KMT2D gene variants.

Genetic analysis of a Chinese family affected with α-dystroglycanopathy due to variant of B3GALNT2 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with recurrent fetal hydrocephalus.@*METHODS@#A couple who had presented at the Affiliated Hospital of Putian College on March 3, 2021 was selected as the study subject. Following elective abortion, fetal tissue and peripheral blood samples were respectively obtained from the abortus and the couple, and were subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing.@*RESULTS@#The fetus was found to harbor compound heterozygous variants of the B3GALNT2 gene, namely c.261-2A>G and c.536T>C (p.Leu179Pro), which were inherited from its father and mother, respectively.According to the guidelines of American College of Medical Genetics and Genomics, both variants were classified as pathogenic (PVS1+PM2_Supporting; PM3+PM2_Supporting+PP3+PP4).@*CONCLUSION@#The compound heterozygous variants of the B3GALNT2 gene probably underlay the α-dystroglycanopathy in this fetus. Above results have provided a basis for genetic counseling of this pedigree.

Clinical manifestations and genetic analysis of 4 patients with variants of FBN1 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for four patients suspected for Marfan syndrome (MFS).@*METHODS@#Four male patients with suspected MFS and their family members who were treated at West China Second Hospital of Sichuan University from September 12, 2019 to March 27, 2021 were selected as the study subjects. Peripheral venous blood samples were collected from the patients and their parents or other pedigree members for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variants were validated by Sanger sequencing. The pathogenicity of the variants was determined based on the guidelines from the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#Genetic testing revealed that all four patients have harbored variants of the FBN1 gene, including c.430_433del (p.His144fs) deletional variant in exon 5, c.493C>T (p.Arg165*) nonsense variant in exon 6, c.5304_5306del (p.Asp1768del) deletional variant in exon 44 and c.5165C>G (p.Ser1722Cys) missense variant in exon 42. According to the ACMG guidelines, the c.430_433del and c.493C>T were classified as pathogenic variants (PVS1+PM2_Supporting+PP4; PVS1+PS1+PS2+PM2_Supporting+PP4). c.5304_5306del and c.5165C>G were classified as likely pathogenic variants (PS2+PM2_Supporting+PM4+PP4; PS2_Moderate+PS1+PM1+PM2_Supporting).@*CONCLUSION@#The c.430_433del and c.5304_5306del variants of the FBN1 gene identified in this study were unreported previously. Above results have enriched the variation spectrum of the FBN1 gene and provided a basis for genetic counseling and prenatal diagnosis of patients with MFS and acromicric dysplasia.

Identification of a NONO gene variant in a child with congenital heart disease and global developmental delay / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with congenital heart disease (CHD) and global developmental delay (GDD).@*METHODS@#A child who was hospitalized at the Department of Cardiac Surgery of Fujian Children's Hospital on April 27, 2022 was selected as the study subject. Clinical data of the child was collected. Umbilical cord blood sample of the child and peripheral blood samples of his parents were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#The child, a 3-year-and-3-month-old boy, had manifested cardiac abnormalities and developmental delay. WES revealed that he had harbored a nonsense variant of c.457C>T (p.Arg153*) in the NONO gene. Sanger sequencing showed that neither of his parents has carried the same variant. The variant has been recorded by the OMIM, ClinVar and HGMD databases, but not in the normal population databases of 1000 Genomes, dbSNP and gnomAD. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), it was rated as a pathogenic variant.@*CONCLUSION@#The c.457C>T (p.Arg153*) variant of the NONO gene probably underlay the CHD and GDD in this child. Above finding has expanded the phenotypic spectrum of the NONO gene and provided a reference for the clinical diagnosis and genetic counseling for this family.