中华医学遗传学杂志最新文献

Objective: To explore the clinical phenotype and pathogenesis of a child with partial duplication in the long arm of chromosome 10 (10q), and conduct a review of relevant literature.

Methods: A child presented at Lianyungang Maternal and Child Health Care Hospital in April 2018 for growth retardation, intellectual disability, and autism spectrum disorder (ASD) was selected as the study subject. Peripheral blood samples were collected from the child and his parents for G-banded chromosomal karyotyping analysis. Genomic DNA was also extracted for chromosomal microarray analysis (CMA). The clinical phenotype and relevant genes were searched in the Online Mendelian Inheritance in Man (OMIM) and the UK Database of Genomic Variation and Phenotype in Humans using Ensembl Resources (DECIPHER). The pathogenicity of chromosomal variation was analyzed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). Relevant literature was searched from the CNKI, Wanfang Data, and PubMed databases by using keywords such as "10q" "duplication" and "trisomy", with the time set as from the establishment of database to December 1, 2023. This study has been approved by the Medical Ethics Committee of the Lianyungang Maternal and Child Health Care Hospital (No. XM2023030).

Results: The clinical phenotype of child had included growth retardation, intellectual disability, and ASD. G-banded chromosomal analysis suggested that the child has a karyotype of 46,XY,dup(10)(q23.31q24.33), whilst both of his parents were normal. CMA analysis of the child revealed that the child was arr[19]10q23.31q24.33(87603382_104948862)×3, with a 17.34 Mb duplication in the 10q23.31q24.33 region. Search of the OMIM database suggested that the duplicated segment has contained 171 genes associated with various diseases, and search of the DECIPHER database has identified cases with overlapping with the duplication. A search of the PubMed database has identified 2 publications involving 2 patients with chromosomal duplications overlapping the 10q23.31q24.33 region with a segment length of > 10 Mb. The 2 patients had mainly manifested growth retardation, intellectual disability, ASD, and facial and limb malformations. The main pathogenic genes had included PTEN, WNT8B, LZTS2, NFKB2, PAX2, KIF11, FRA10AC1, and CNNM2. No similar case was retrieved from the CNKI and Wanfang Data databases.

Conclusion: The partial 10q duplication as a novel CNV involving genes such as PTEN and WNT8B probably underlay the growth retardation, intellectual disability and ASD in child 1 . This study has enriched the genotype-phenotype spectrum of patients with partial 10q23.31q24.33 duplications.

Objective: To investigate the serological and molecular genetic characteristics of a voluntary blood donor with combined FUT1 and ABO blood group gene variants causing para-Bombay and A2 subtype, and to review relevant literature on para-Bombay blood types carrying alleles such as FUT101W.37 and FUT101W.23.

Methods: A blood donor with para-Bombay and A2 subtype who participated in voluntary blood donation at the Dongguan Blood Center in August 2023 was selected as the study subject. Serological tests were performed to identify the ABO blood group, Lewis blood group antigens, and unexpected serum antibodies in the donor. Adsorption-elution test was conducted to detect trace antibodies in the blood donor's plasma to trace the A, B and H antigens on the red blood cell surface. Sanger sequencing was carried out to analyze the sequences of the FUT1 and ABO genes. Using keywords such as "para-Bombay" "FUT1*01W.37" and "FUT1*01W.23" both in Chinese and English, relevant literature on para-Bombay blood type subjects carrying FUT1*01W.37 and FUT1*01W.23 alleles was retrieved from the CNKI, Wanfang Data Knowledge Service Platform, and PubMed databases, and the retrieval time was set as from the establishment of database to December 2022. This study has been approved by the Ethics Committee of Dongguan Blood Center (No. 2022005), and informed consent of blood donation was obtained from the blood donor.

Results: Serological testing of the blood donor revealed inconsistent results between forward and reverse ABO blood typing, negative H antigen on the red blood cell surface, Le(a-b+) secretor type for Lewis blood group, and unexpected anti-H antibodies in the plasma, indicating a suspected para-Bombay type. Absorption-elution test suggested the blood type of the blood donor to be para-Bombay and A subtype. Sanger sequencing showed that the donor has harbored homozygous FUT1*(c.35T+c.803A)/(c.35T+c.803A) variant, with the FUT1*(c.35T+c.803A) allele containing a dual nucleotide variant unrecorded by the International Society of Blood Transfusion (ISBT) FUT1 gene variant database, which was similar to the weakly functional allele of FUT101W. 37(c.803G>A) as recorded by the ISBT database. The ABO genotype was heterozygous ABOA2.05/O.01.02. Combining the results of serological and genetic testing, the blood type of the blood donor was determined to be para-Bombay and A2 subtypes. Literature review has identified a pregnant women from Qingdao carrying the FUT1*01W.37 allele and 2 individuals carrying a heterozygous FUT1*01W.23 allele.

Conclusion: This study has discovered a blood donor with coexisting para-Bombay and ABO subtype blood groups. Based on the characteristics of red blood cell surface antigens, the FUT1*01W.37 as classified as an FUT1 null allele.

Objective: To explore the value of applying multiple genetic testing techniques for the prenatal diagnosis of Turner syndrome fetuses with complex mosaic small supernumerary marker chromosomes (sSMC).

Methods: Chromosomal karyotypes of amniotic fluid samples from 5 030 pregnant women who had undergone amniocentesis at the Prenatal Diagnosis Center of the Third Affiliated Hospital of Zhengzhou University from January to December 2022 were retrospectively reviewed. Three fetuses with complex mosaicism fetuses (carrying 2 types of sSMC) were selected as the study subjects. Genetic tests including G-banded chromosomal karyotyping analysis, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and copy number variation sequencing (CNV-seq) were used to clarify the origin and mosaic status of the sSMC. This study has been approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (No. 2023-159-01).

Results: G-banded chromosomal analysis of fetus 1 showed a karyotype of 45,X[64]/46,X,+mar1[13]/46,X,+mar2[3]. FISH results showed that 52% of of its cells had contained one X chromosome signal, whilst 48% contained two X chromosome signals. CMA results revealed the fetus had harbored a 32.32 Mb and a 50.93 Mb deletion in Xp22.33p21.1 and Xq22.2q28 regions, respectively, in addition with mosaic deletions of approximately 1.43 copies, 1.78 copies and 1.43 copies in the Xp21.1p11.1, Xq11.1q21.1 and Xq21.2q22.2 regions, respectively. The fetus 2 had a karyotype of 45,X[27]/46,X,+mar1[14]/46,X,+mar2[12]. FISH results indicated that 88% of its cells contained one X chromosomes signal and two Y chromosome signals, and 12% contained signals for one X chromosomes signal and one Y chromosome signal. CNV-seq results revealed a deletion of 7.74 Mb in the Yq11.222q11.23 region and a mosaic duplication of approximately 1.738 copies in the Yp11.31q11.221 region. The fetus 3 had a karyotype of 45,X[60]/46,X,+mar1[11]/46,X,+mar2[6]. FISH results showed that 28% of its cells contained one X chromosome signal, and 72% contained tow X chromosome signals. CNV-seq results revealed deletions of 55.60 Mb and 53.50 Mb in the Xp22.33p11.1 and Xq22.1q28 regions, respectively, along with a mosaic deletion of approximately 1.85 copies in the Xp11.1q13.2 region and a mosaic repeats of approximately 2.66 copies in the Xq13.2q22.1 region. The sSMCs in the 3 fetuses had all originated from sex chromosomes and were of complex mosaic type. After genetic counseling, the three couples had all opted to terminate the pregnancy.

Conclusion: The combined use of multiple genetic testing techniques has determined the origin and structure of complex mosaic sSMCs and provided a basis for prenantal diagnosis and genetic counseling.

Objective: To analyze the clinical characteristics of a child with Congenital disorder of glycosylation due to compound heterozygous variants of COG6 gene (COG6-CDG).

Methods: A child who was admitted to Xi'an Children's Hospital on January 10, 2023 was selected as the study subject. Clinical data were collected. Pathogenic variants were analyzed by whole exome sequencing, and candidate variants were verified by Sanger sequencing, in vitro experiments and bioinformatic analysis. This study was approved by the Medical Ethics Committee of Xi'an Children's Hospital (Ethics No. 20230101).

Results: The child, a 1-month-8-day-old male, was admitted for diarrhea and weight loss for one month. He had presented with cholestasis, diarrhea, facial dysmorphism, poor response, bilateral Simian crease, and brain atrophy. After discharge, he had continued to have high fever, feeding difficulty, and deceased finally. Whole exome sequencing results showed that he had harbored compound heterozygous variants of the COG6 gene, namely c.807delT (p.F269Lfs*37) and c.1746+1G>C (p.Gly565_Met582del). Sanger sequencing verified that the variants were inherited from his father and mother, respectively. In vitro experiments verified that the c.1746+1G>C variant could affect the mRNA splicing and produce a truncated protein, whilst the c.807delT variant could significantly reduce gene expression at both mRNA and protein levels. Based on the guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP), the variants were classified as pathogenic (PVS1+PM3+PM2_Supporting) and likely pathogenic (PVS1+PM2_Supporting), respectively.

Conclusion: The c.807delT (p.F269Lfs*37) and c.1746+1G>C (p.Gly565_Met582del) compound heterozygous variants of the COG6 gene probably underlay the pathogenesis of this child. Above finding has enriched the mutational spectrum of COG6-CDG and provided a basis for the genetic counseling for this family.

Objective: To explore the genetic etiology and clinical phenotype of a child with Triadin knockout syndrome (TKOS), and to review the relevant literature of TKOS patients due to variants of TRDN gene.

Methods: A child who was admitted to the Children's Hospital of Xi'an Jiaotong University on March 19, 2023 due to sudden cardiac arrest 3 days earlier was selected as the study subject. Peripheral blood samples (2 to 3 mL) were collected from the child and her parents for the extraction of genomic DNA and whole exome sequencing (WES). Pathogenic variants were searched from databases such as the Genome Aggregation Database (gnomAD) and Online Mendelian Inheritance in Man (OMIM), and were assessed based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Sanger sequencing was carried out for family validation of the pathogenic variants. Using keywords such as "arrhythmias" "TRDN" and "Triadin" both in Chinese and English, relevant literature on TKOS patients due to variants of the TRDN gene was retrieved from the CNKI, Wanfang Data Knowledge Service Platform, and PubMed databases, and the time of literature retrieval was set from January 1, 2012 to December 1, 2023. This study has been approved by the Ethics Committee of the Affiliated Children's Hospital of Xi'an Jiaotong University (No. 20230097), and informed consent was obtained from the parents of the child.

Results: The child had experienced syncope and cardiac arrest after exercise. Electrocardiographic examination revealed QTc interval prolongation, T-wave inversion in precordial leads V1-V3, polymorphic ventricular premature beat (VPB), and ventricular tachycardia (VT) along with increased heart rate. WES and Sanger sequencing revealed that the child has harbored a homozygous c.463del(p.E155Kfs*20) variant of the TRDN gene, for which both of the parents were heterozygous. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+PM2+PM3). The child was ultimately diagnosed with TKOS. In total 12 publications on TOKS cases caused by TRDN gene variants were retrieved, which involved 30 patients and 28 carriers of single heterozygous variant of the TRDN gene. Among the 30 TKOS patients, 20 had carried homozygous variants of the TRDN gene, and 10 had carried compound heterozygous variants, and all had exhibited significant clinical phenotype of arrhythmia, with most cases had experienced malignant arrhythmia induced by exercise and/or excitement during infancy or early childhood, leading to recurrent syncope and cardiac arrest. Of note, none of the 28 carriers of single heterozygous variant had abnormal clinical phenotype.

Conclusion: The homozygous c.463del(p.E155Kfs20) variant of the TRDN gene probably underlay the pathogenesis of cardiac arrest in this child. Above discovery has enriched the mutational spectrum of the TRDN gene.

Objective: To summarize the clinical manifestations of Autosomal dominant complex neurodevelopmental disorders due to variants of EEF1A2 gene and explore their pathogenic mechanisms.

Methods: A child who had visited Luoyang Maternal and Child Health Care Hospital in July 2021 for global developmental delay was selected as the study subject. Clinical data of the child was reviewed. The child was subjected to whole exome sequencing, and relevant literature was reviewed. This study has been approved by the Medical Ethics Committee of Luoyang Maternal and Child Health Care Hospital (No. YCCZ-KS-KY-2021-03).

Results: The patient, a 2-year-and-4-month-old girl, had presented with global developmental delay, gait instability, low limb muscle strength, and absence language development. Her parents were both healthy and denied relevant family history. Genetic testing revealed that she has harbored a de novo heterozygous c.44A>G (p.H15R) missense variant of the EEF1A2 gene (NM_001958.5), which was unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was rated as pathogenic.

Conclusion: The c.44A>G (p.H15R) variant of the EEF1A2 gene probably underlay the pathogenesis in this patient. Above finding has also enriched the mutational spectrum of the EEF1A2 gene.

The "Developmental Origins of Health and Disease, DOHaD" theory suggests that adverse factors in early life can lead to the occurrence of chronic diseases in adulthood. In recent years, it has been discovered that maternal factors, intrauterine development environment and environmental exposure during pregnancy can mediate the changes of early egg/embryo development, promote the occurrence of reproductive disorders such as polycystic ovary syndrome, diminished ovarian reserve, and endometriosis, and induce intergenerational genetic effects. This article has reviewed the progress of research on maternal factors which may affect the pathogenesis of reproductive disorders, and expounds its mechanism from the perspectives of epigenetic mechanisms such as DNA methylation, histone modification and non-coding small RNA (miRNA) modification, with an aim to provide insights for studying the occurrence of adult reproductive disorders in early life and before pregnancy.

Objective: To explore the genetic etiology of a pedigree with intellectual disability and explore its pathogenesis.

Methods: A Chinese pedigree which had presented at the Henan Provincial People's Hospital in March 2023 was selected as the study subject. Clinical data of the pedigree were collected, along with peripheral venous blood samples from its members. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing. Amniotic fluid was collected for prenatal diagnosis. This study was approved by the Medical Ethics Committee of the Henan Provincial People's Hospital (Ethics No. 2019-134).

Results: Both the proband (a 6-year-old male) and his mother (30 years old) had various degrees of intellectual and motor impairment. WES revealed that the proband has harbored a de novo heterozygous c.2563_2567dup (p.Lys856fs) variant of the UBE3A gene, while his mother, maternal grandmother and fetus had all harbored a novel heterozygous c.409+1G>A variant of the RNF13 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS1+PS1+PM2_Supporting; PVS1+PM2_Supporting+PP3).

Conclusion: Based on the clinical manifestations and the result of genetic testing, the heterozygous c.2563_2567dup (p.Lys856fs) variant of the UBE3A gene probably underlay the intellectual disability and developmental delay in the proband, whilst the heterozygous c.409+1G>A variant of the RNF13 gene may underlie the intellectual disability in the proband's mother and grandmother. Above results have enabled genetic counseling and prenatal diagnosis for this pedigree.

Objective: To explore the clinical and genetic characteristics of a child with autosomal recessive primary microcephaly (MCPH).

Methods: A case study has been carried out on a boy who had presented at the Inner Mongolia Maternity and Child Health Care Hospital for microcephaly and mental deficiency in September 2022. Prenatal ultrasound images were retrospectively analyzed, and whole exome sequencing and Sanger sequencing were carried out for his family. A literature review was also carried out using keywords such as "ASPM gene", "microcephaly", "prenatal diagnosis", "primary microcephaly", "ASPM", "MCPH5", "MCPH", "autosomal recessive microcephaly", and "prenatal diagnosis on ultrasonography" on the PubMed database, Wanfang Data and China National Knowledge until September 2023. This study was approved by the Inner Mongolia Maternity and Child Health Care Hospital (Ethics No. 2021-093-1).

Results: The proband had shown progressive reduction in biparietal diameter (BPD) and head circumference (HC) during the fetal period. He was found to harbor compound heterozygous variants of the ASPM gene, which included a paternally derived c.8044C>T (p.R2682X) and a maternally derived c.8652dup (p.A2885Sfs*35). Both variants were classified as pathogenic (PVS1+PM2_Supporting+PP4; PVS1+PM2_Supporting+PM3) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). For other fetuses in his family, prenatal ultrasound and genetic testing were all normal. Literature research has identified 11 relevant articles, which included 14 MCPH cases. All of the MCPH5 cases had shown various degrees of reduced BPD/HC on fetal imaging (100%, 15/15). Developmental delay, intellectual disability, and attention deficits were noted in all survived cases, with one case having seizures (12.5%, 1/8). Their genotypes had included homozygotes (46.2%, 6/13) and compound heterozygotes (53.8%, 7/13) for nonsense variants (45%, 9/20) and frameshifting variants (55%, 11/20).

Conclusion: The compound heterozygous variants c.8044C>T (p.R2682X) and c.8652dup (p.A2885Sfs*35) of the ASPM gene probably underlay the reduced BPD and HC in this proband with MCPH.

Objetive: To explore the clinical and genetic etiology of a Chinese pedigree affected with type 2 Long QT syndrome (LQTS).

Methods: A pedigree with type 2 LQTS presented at Fuwai Central China Cardiovascular Hospital on August 23, 2019 was selected as the study subject. Peripheral blood samples were collected from the proband and her parents. Following extraction of genomic DNA, whole exome sequencing (WES) was carried out for the proband, and candidate variant was screened through functional annotation and protein-protein interaction (PPI) analysis. Sanger sequencing was conducted to verify the pathogenicity of candidate variant. This study was approved by the Fuwai Central China Cardiovascular Hospital (Ethics No. 2019-15).

Results: WES revealed that the proband has harbored a missense variant of the KCNH2 gene, namely c.1478A>G (p.Tyr493Cys), which was confirmed by Sanger sequencing to have inherited from her father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PM2_supporting+PM5+PP3+PP4).

Conclusion: The KCNH2 gene c.1478A>G (p.Tyr493Cys) variant probably underlay the type 2 LQTS in this pedigree.