中华医学遗传学杂志最新文献

Objective: To explore the prenatal and postnatal features and genetic characteristics of patients with Lymphedema-Distichiasis syndrome (LDS) due to variants of FOXC2 gene.

Methods: A retrospective analysis was carried out on the phenotypic information, fetal ultrasound image, and genetic testing of two Chinese pedigrees diagnosed at the Third Affiliated Hospital of Zhengzhou University. A literature review was also carried out by searching the China National Knowledge Infrastructure (CNKI), Wanfang Database, and PubMed databases dated from January 2010 to June 2024 using keywords "Lymphedema-Distichiasis syndrome " and "FOXC2 ". This study has been approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-046-01).

Results: Neither family was found to harbor chromosomal aneuploidy or pathogenic CNVs larger than 100 kb. The fetuses from pedigree 1 and pedigree 2 were respectively found to be heterozygous for a c.361C>T (p.R121C) variant and a c.168C>A (p.Y56*) variant of the FOXC2 gene. Both variants were paternally derived. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were classified as pathogenic and likely pathogenic, respectively. Literature search has identified 20 articles, and combined with our cases, a total of 117 patients were identified. Among them, 13 had shown prenatal phenotypes, primarily with increased nuchal translucency (NT) (12/13), urinary abnormalities (5/12), and fetal edema (4/13). Postnatal phenotypes were observed in 110 cases, mainly as distichiasis (87/110) and lymphedema (73/110). Only 6 cases had both prenatal and postnatal phenotypes. A total of 32 genetic variants were identified.

Conclusion: The primary prenatal manifestations of LDS include increased NT, fetal edema, pleural and abdominal effusion, and separation of renal collecting system. Postnatal phenotypes are primarily characterized by lymphedema, distichiasis, and spinal extradural arachnoid cysts. Discovery of the c.168C>A variant has expanded the spectrum of FOXC2 gene mutations in China.

Objetive: To explore the clinical manifestations and genetic etiology of a Chinese pedigree affected with Familial focal epilepsy with variable foci (FFEVF).

Methods: A FFEVF pedigree presented at the Department of Medical Genetics of Linyi Maternal and Child Health Care Hospital on March 14, 2023 was selected as the study subject. The proband was subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing of the proband and other affected members and bioinformatic analysis. This study was approved by the Linyi Maternal and Child Health Care Hospital (Ethics No. QTL-YXLL-2023048).

Results: WES revealed that the proband has harbored a heterozygous c.1642C>T (p.Arg548Cys) missense variant in exon 15 of the NPRL3 gene. Sanger sequencing confirmed that the variant was inherited from the proband's father, and multiple members of the pedigree had also harbored the same variant. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as variant of unknown significance (PM2_supporting + PP3).

Conclusion: The clinical phenotype of FFEVF patients caused by variants of NPRL3 gene is extensive, and the patients may present with neurological abnormality of autism spectrum disorder in addition to seizures.

Objective: To explore the genetic etiology and clinical outcome of a child with co-morbid progressive IgA nephropathy and COQ8B-associated glomerulopathy.

Methods: A child who was admitted to Peking University First Hospital on March 2, 2021 was selected as the study subject. Genomic DNA was extracted from peripheral blood samples from the child and his parents and sister. Whole exome sequencing was carried out, and candidate variant was verified by Sanger sequencing. This study was approved by the Peking University First Hospital (Ethics No. 2016[1029]).

Results: The child, a 7-year-old boy who had developed proteinuria 8 months before, was diagnosed with IgA nephropathy (M1E1S1T1C1). With steroid, cyclophosphamide, cyclosporine and angiotensin-converting enzyme inhibitor therapy, partial remission of proteinuria was achieved. However, his serum creatinine level had increased from 53.8 mol/L at the onset of disease to 86.7 mol/L after 3.9 years, along with massive proteinuria. Kidney biopsy still indicated IgA nephropathy (M0E0S1T0C0). The child was found to harbor a homozygous c.737G>A (p.Ser246Asn) missense variant of the COQ8B gene, for which his parents and sister were heterozygous carriers. The variant was predicted to be pathogenic (PS1+PM2_Supporting+PM3+PP3+PP4) based on the guidelines from the American College of Medical Genetics and Genomics. The child was treated with high-dose coenzyme Q10 in combination with steroid and/or mycophenolate mofetil, though his serum creatinine level still increased to 286 mol/L after 7.3 years, which conformed to a chronic kidney disorder with glomerular filtration rate category of G3b.

Conclusion: The homozygous c.737G>A missense variants of the COQ8B gene probably underlay the progressive kidney dysfunction in this child. For children with IgA nephropathy presenting with atypical clinical manifestations, unsatisfactory therapeutic effect, and/or early onset of kidney function decline, coexistence of other diseases should be suspected.

Objective: To carry out genetic testing on a child diagnosed with Very-long-chain acyl-CoA dehydrogenase deficiency (VLADD) in order to provide a basis for genetic counseling and prenatal diagnosis for his family.

Methods: Whole exome sequencing was performed for the proband. Candidate variant sites in the ACADVL gene were verified by Sanger sequencing, and their pathogenicity was predicted based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was performed on the fetus upon subsequent pregnancy. This study was approved by the Luoyang Maternal and Child Health Care Hospital (Ethics No. ).

Results: The proband was found to harbor compound heterozygous variants of the ACADVL gene, namely c.1532G>A and 1827+2_1827+12del, which were inherited from his mother and father, and classified as likely pathogenic and pathogenic, respectively. By combining the clinical manifestations of the proband and the results of blood tandem mass spectrometry and genetic testing, the child was ultimately diagnosed as cardiomyopathy type VLADD. Prenatal diagnosis showed that the fetus has carried the same compound heterozygous variants, and the couple had opted to terminate the pregnancy.

Conclusion: The c.1532G>A/1827+2_1827+12del compound heterozygous variants of the ACADVL gene probably underlay the pathogenesis of VLADD in this pedigree. The discovery of the 1827+2_1827+12del variant has enriched the mutational spectrum of the ACADVL gene.

Objective: To explore the clinical characteristics and genetic etiology of a child with Spondyloocular syndrome (SOS) in order to enhance the awareness and understanding of this disease.

Methods: A 3.5-year-old boy with SOS who had presented at the Department of Medical Genetics of Hunan Children's Hospital on August 10, 2023 due to the repeated fractures for over 2 years and after binocular cataract surgery was selected as the study subject. Clinical data of his pedigree were collected, and peripheral venous blood samples were collected for the extraction of genomic DNA and subjected to trio-whole exome sequencing. Candidate variants were verified by Sanger sequencing and analyzed with bioinformatic software. This study was approved by the Medical Ethics Committee of Hunan Children's Hospital (Ethics No. KYAQ2022-263).

Results: The child had manifested repeated fractures, bilateral bowed femur, osteoporosis, cataract, atrial septal defect, and developmental delay. Ultrasonography has revealed fetal edema, peritoneal effusion, pleural effusion and polyhydramnios. Trio-whole exome sequencing and Sanger sequencing revealed that he has harbored compound heterozygous variants of the XYLT2 gene, namely c.1103_1104delAG (p.Gln368Argfs*8) and c.1238_1253delinsA (p.Val413_Pro418delinsGlu), which were inherited from his phenotypically normal father and mother, respectively. Neither variant was reported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and recommendations from the Clinical Genome Resource (ClinGen), the c.1103_1104delAG was predicted as a pathogenic variant (PVS1+PM2_Supporting+PP4), whilst the c.1238_1253delinsA was predicted as a likely pathogenic variant (PM4+PM3+PM2_Supporting+PP4).

Conclusion: The c.1103_1104delAG and c.1238_1253delinsA compound heterozygous variants of the XYLT2 gene probably underlay the pathogenesis in this child. Above finding has enriched the phenotypic and mutational spectrum of SOS, and provided a basis for the clinical diagnosis, treatment, prognosis assessment and genetic counseling for this pedigree.

Objective: To explore the clinical characteristics and pathogenic variant in a child with Cantú syndrome (CS).

Methods: A male who was admitted to the Children's Hospital Affiliated to Zhengzhou University on February 23, 2022 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 whole-exome sequencing (WES). Candidate variant was verified by Sanger sequencing. This study was approved by the Children's Hospital Affiliated to Zhengzhou University (Ethics No. 2023-K-087).

Results: The child, a 3-year-and-2-month-old male, was born with hirsutism, with heavy hair all over the body and peculiar facial features. Routine echocardiography 1 month before had discovered atrial septal defect. Sequencing revealed that the child has harbored a heterozygous c.2438G>C (p.S813T) variant of the ABCC9 gene, which was de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2438G>C variant was classified as likely pathogenic (PS2+PM2_Supporting+PP3).

Conclusion: The heterozygous c.2438G>C variant of the ABCC9 gene probably underlay the pathogenesis of CS in this child.

Objective: To explore the genetic etiology of a fetus with Coffin-Siris syndrome (CSS).

Methods: A fetus with abnormal ultrasound findings detected at Luoyang Maternal and Child Health Care Hospital in July 2023 was selected as the study subject. Clinical data were analyzed retrospectively. Whole exome sequencing was carried out on fetal tissue and parental peripheral blood samples, and candidate variant was verified by Sanger sequencing and pathogenicity analysis. This study was approved by the Luoyang Maternal and Child Health Care Hospital (Ethics No. LYFY-YCCZ-2023011).

Results: Color Doppler ultrasound at 16⁺ gestational weeks revealed bilateral ventriculomegaly and cerebellar hypoplasia in the fetus. Trio-WES found that the fetus has harbored a heterozygous c.553C>T (p.Gln185Ter) variant of the ARID1A gene, which was verified by Sanger sequencing to have a de novo origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.553C>T (p.Gln185Ter) variant of the ARID1A gene was classified as pathogenic (PVS1+PS2_Supporting+PM2_Supporting).

Conclusion: The fetus was diagnosed with CSS type 2, and the heterozygous c.553C>T (p.Gln185Ter) variant of the ARID1A gene probably underlay its brain malformations.

Objetive: To explore the clinical and molecular basis for a Chinese pedigree affected with Complete androgen insensitivity syndrome (CAIS).

Methods: A CAIS pedigree presented at Tianjin Medical University General Hospital between 2019 and 2021 was selected as the study subject. Clinical data of the proband was collected, along with peripheral blood samples from the proband and her family members. Chromosomal karyotyping, sex-determining region of the Y chromosome (SRY) testing, and next-generation sequencing (NGS) were carried out for the proband, and candidate variant was verified by Sanger sequencing of her family members. Prenatal diagnosis was provided for the sister of the proband. This study was approved by the Tianjin Medical University General Hospital (Ethics No. IRB2023-WZ-070).

Results: The 18-year-old proband, who has a social gender of female, underwent laparoscopic examination, which showed no presence of uterus and ovaries. The karyotype of peripheral blood sample was 46,XY, with SRY gene detected. NGS indicated that the proband has harbored a heterozygous c.1988C>G (p.Ser663Ter) variant of the AR gene. Sanger sequencing confirmed that her mother and sister had both harbored the same variant, whilst her father and younger sister were of the wild-type. Prenatal diagnosis revealed that her sister's first fetus had harbored carried the same variant, which had led to termination of pregnancy. Her second fetus did not carry the variant, and a healthy boy was born. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PM2_Supporting+PM4+PP3_Moderate+PP4).

Conclusion: The c.1988C>G (p.Ser663Ter) variant of the AR gene probably underlay the CAIS in the proband. The accurate diagnosis of sex development disorders will rely on the physicians' thorough understanding of the clinical symptoms and pathogenic genes. Genetic testing and counseling can enable precise diagnosis, prenatal diagnosis, and guidance for reproduction.

Objetive: To explore the hematological phenotype and genotypic characteristics of five Chinese individuals with a rare thalassemia mutation HBB: c.93-21G＞A.

Methods: A retrospective study was carried out on five individuals identified by the People's Hospital of Yangjiang and Guangzhou Hybribio Co., Ltd. from May 2018 to September 2022. Routine blood test and hemoglobin electrophoresis were performed, and the genotypes of five subjects were determined by using PCR combined with reverse dot blotting (RDB), nested PCR, Gap-PCR and Sanger sequencing. This study was approved by the People's Hospital of Yangjiang (Ethics No. 20240001).

Results: Among the five individuals, hematological data of one was unavailable, and the remaining four had presented with microcytosis and hypochromia. The results of hemoglobin electrophoresis indicated that all of them had a HbA2 level of ≥4.7%. Genetic analysis showed that one case had harbored compound heterozygous mutations of ααα^anti3.7 triplet and HBB: c.93-21G＞A, one had compound heterozygous mutations of -α^3.7 and HBB: c.93-21G＞A, whilst the remaining three were heterozygous for the HBB: c.93-21G＞A mutation.

Conclusion: The hematological phenotype of β-thalassemia carriers (HBB: c.93-21G＞A) is similar to that of other β⁺ thalassemia heterozygotes with mild β-thalassemia characteristics.

Objetive: To explore the clinical and genetic characteristics of two children with Neurodevelopmental disorders (NDDs) due to variants of TANC2 gene.

Methods: Clinical data of two children who were admitted to the Third Affiliated Hospital of Zhengzhou University respectively in April 2020 and April 2021 were retrospectively analyzed. Peripheral blood samples of the children and their parents were collected and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. By using "TANC2 gene", "Neurodevelopmental disorders", "Nervous system development disorders", "TANC2" as the key words, similar cases were searched from the CNKI, Wanfang database platform and PubMed database, with the search time set as from the establishment of the database to December 2023. This study was approved by the Third Affiliated Hospital of Zhengzhou University (Ethics No. 2020-57).

Results: Case 1 was a 1-year-and-3-month-old girl who had developed convulsions at 1 year old and had three episodes of seizures. Her epilepsy had resolved with the treatment of oxcarbazepine, which was stopped at the age of 2-year-and-7-month. Her language, movement and intelligence development were all normal. Case 2 was a 1-year-and-10-month-old boy, who had developed convulsions at 1 year old. His seizure type was myoclonus, and the frequency was dozens of times a day. His epilepsy had resolved with the treatment of sodium valproate. His language, movement and intelligence development was delayed for about half a year. Genetic analysis showed that both children had harbored novel variants of the TANC2 gene (NM_025185.4), including c.3398G>A (p.Gly1133Glu) and c.2829+1G>A, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the former was rated as likely pathogenic (PS2+PM2_Supporting+PP3) and the latter was rated as pathogenic (PVS1+PS2+PM2_Supporting). Two previous reports were retrieved, which had involved 17 cases and 16 variants. Common features had included autism spectrum disorder (70.6%, 12/17) , intellectual disability (94.1%,16/17) , language and motor retardation (88.2%, 15/17；58.8%, 10/17), facial dysmorphism, epilepsy, ataxia, and thoracic and spinal deformities.

Conclusion: Variants of the TANC2 gene probably underlay the epilepsy and development delay in these children with NDDs.