中华医学遗传学杂志最新文献

Objective: To explore the clinical presentation and genetic etiology of a case with Xeroderma pigmentosum in conjunct with basal cell carcinoma and melanoma.

Methods: A male patient with Xeroderma pigmentosum treated at Xinxiang Central Hospital in October 2022 was selected as study subject. Whole exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing of his family members. This study was approved by the Ethics Committee of the hospital (Ethics No.: 2021-167).

Results: Magnetic resonance imaging showed that the patient has a solid soft tissue mass in the anterior and lower part of his right eyeball and a small nodule on the left nasal wing. Histopathological biopsy showed that the periocular tumor was basal cell carcinoma in conjunct with malignant melanoma, and the nasal wing tumor was basal cell carcinoma. WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the XPC gene, namely c.2391delT (p.F797Lfs*11) and IVS1+1G>A, which were inherited from his father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were rated as likely pathogenic (PVS1+PM2_Supporting+PM3) and pathogenic (PVS1+PM2_Supporting+PM3+PP5), respectively. The c.2391delT variant was unreported previously. Bioinformatic analysis suggests that it could significantly affect the tertiary structure of XPC protein.

Conclusion: The c.2391delT(p.F797Lfs*11) and IVS1+1G>A compound heterozygous variants probably underlay the pathogenesis in this patient. The detection of the novel variant has enriched the mutational spectrum of the XPC gene.

Objective: To analyze the phenotype and genotype of a family with hereditary coagulation factor Ⅹ (FⅩ) deficiency and preliminarily explore its molecular pathogenesis.

Methods: A hereditary FⅩ deficiency pedigree presented at the First Affiliated Hospital of Wenzhou Medical University on August 13, 2024 was selected as the study subject. Coagulation parameters of the proband and her family members (7 individuals from 3 generations) were measured using a one-stage clotting assay. All of the 8 exons and flanking sequences of the F10 gene were amplified by PCR and directly sequenced. Bioinformatics software was used to analyze the functional impact and pathogenicity of the variant proteins, as well as the spatial conformational changes and evolutionary conservation of the mutation sites. This study has been approved by the Medical Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (Ethics No.: KY2022-R193).

Results: The proband exhibited significantly abnormal prothrombin time (PT, 33.3 s), activated partial thromboplastin time (APTT, 47.7 s), and FⅩ activity (FⅩ:C, 3%), while other coagulation parameters remained normal. The plasma thromboplastin generation test (PTGT) demonstrated that the proband and her children had lower thromboplastin generation levels compared with the healthy control group, and the proband's thromboplastin generation capacity was more severely impaired. Genetic analysis revealed that the proband, her daughter, and grandson have all harbored a heterozygous missense variant c.212T>C (p.Phe71Ser) in exon 2 of the F10 gene, which was located in the β-sheet core region of the Gla domain. The variant has altered surrounding hydrogen bonds and disrupted calcium-binding sites. Additionally, the proband, her son, and granddaughter have all carried a heterozygous missense variant c.1270G>T (p.Val424Phe) in exon 8, which increased the side-chain volume, leading to steric hindrance in the catalytic domain and impaired coagulation function. Bioinformatics analysis confirmed that both p.Phe71Ser and p.Val424Phe were pathogenic variants, with Phe71 and Val424 being highly conserved residues.

Conclusion: The reduced FⅩ levels in this hereditary FⅩ-deficient family may be attributed to the heterozygous missense variants c.212T>C (p.Phe71Ser) in the exon 2 and c.1270G>T (p.Val424Phe) in the exon 8 of the F10 gene.

Objective: To explore the clinical and genetic characteristics of a child with intellectual development disorder and seizures due to a variant of AP2M1 gene.

Methods: Clinical data of a child with intellectual development disorder and epilepsy who was admitted to the Department of Pediatric Neurology of the Third Affiliated Hospital of Zhengzhou University in January 2021 were retrospectively analyzed. Peripheral blood samples of the child and his parents were collected for whole exome sequencing. Candidate variant was verified by Sanger sequencing and pathogenicity analysis. The three-dimensional structure of the AP2M1 protein was visualized using Chimera v1.10.1 software. Pathogenicity of candidate variant was classified according to the Standards and Guidelines for the Interpretation of Sequence Variants from the American College of Medical Genetics and Genomics American College of Medical Genetics (ACMG). With "AP2M1 gene" "epilepsy" "intellectual disability" as the keywords, relevant cases were searched from CNKI, Wanfang Data knowledge service platform and PubMed databases with the search time spanning from the establishment of the database to September 2024. This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethics No.: 2020-57).

Results: The child was a 8-years-and-6-months-old boy, who could raise his head at 3 months and sit alone at 8 months old. He could not walk alone at 1 year old and underwent 2 months' rehabilitation treatment, and could walk alone and call his parents at 1-and-a-half-years-old. At 4-years-and-10-months-old, he started to have frequent seizures, manifesting as low level of consciousness, body shaking, accompanied by blinking, lasting about a few seconds several times a day and could be relieved. With the treatment of sodium valproate combined with lamotrigine, the convulsions were controlled, but his movement and cognition were lagged behind. DNA sequencing revealed that he has harbored a novel variant of the AP2M1 gene (NM_004068.3) c.508C>T (p.Arg170Trp). Sanger sequencing confirmed that both of his parents were of the wild-type. According to the guidelines from the American College for Medical Genetics and Genomics (ACMG), the variant was rated as pathogenic (PS2+PS4+PM1+PM2+PP2+PP3). The difference between the wild-type and mutant AP2M1 proteins can be clearly viewed through its three-dimensional structure. Two previous reports have included 5 cases due to the same variant. Common manifestations have included seizures (100%, 5/5), motor retardation (100%, 5/5), intellectual impairment (100%, 5/5), autism spectrum disorder (60%, 3/5), ataxia (100%, 5/5), and special facial features (20%, 1/5).

Conclusion: The c.508C>T (p.Arg170Trp) variant of the AP2M1 gene may underlie the intellectual retardation and seizure in this child.

Objective: To investigate the clinical characteristics and genetic etiology of eight members from a pedigree affected with epidermolysis bullosa (EB).

Methods: A girl presented with recurrent, unexplained blisters on the palmar and plantar skin for 8 years and sought medical care in October 2024 was enrolled as the study subject. A retrospective study was conducted to collect the child's clinical data, and a detailed medical history was taken for her family members. Peripheral venous blood samples were collected from the child and her parents for genomic DNA extraction. Whole-exome sequencing (WES) was performed. Candidate variant was validated by Sanger sequencing. The pathogenicity of the candidate variants was classified in accordance with the Standards and Guidelines for the Interpretation of Sequence Variants issued by the American College of Medical Genetics and Genomics (ACMG, hereinafter referred to as the "ACMG Guidelines"). This study was approved by the Medical Ethics Committee of the 980th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army (Ethics No.: 2019-KY-01).

Results: The proband was an 8-year-and-4-month-old female. Four months after birth, she had developed recurrent blisters on the palmar and plantar skin without obvious triggers, accompanied by significant pain. Symptoms were more severe in summer and slightly relieved in winter. Although symptomatic treatment could alleviate the symptoms, she was unable to participate in physical activities. A detailed family history revealed that her great-grandfather, grandfather, father, half-brother, great-aunt, great-aunt's son and two grandsons, as well as her aunt and aunt's son, had similar clinical manifestations. WES revealed that she has harbored a heterozygous c.556-16(IVS1)C>G (NM_000424.4) variant in the KRT5 gene, which was identified as a splice site mutation. Reverse transcription sequencing confirmed that this variant can disrupt normal splicing, resulting in retention of a 15 bp sequence in the first intron. Sanger sequencing demonstrated that the variant was inherited from the father, and the 6 aforementioned relatives with similar phenotypes have all carried the same variant (the great-grandfather, grandfather, and great-aunt had declined genetic testing due to advanced age). Based on the ACMG guidelines, this variant was classified as pathogenic (PS3+PM2_Supporting+PP3+PP1_strong).

Conclusion: Patients with epidermolysis bullosa simplex may exhibit clinical features including blistering on the skin or mucous membranes of friction-prone sites (e.g. hands, feet, elbows, and knees) following minor trauma or friction, as well as increased skin fragility. The c.556-16(IVS1)C>G (rs376462752) variant of the KRT5 gene probably underlay the pathogenesis of EB in this child. Above findings have enriched the mutational spectrum of the KRT5 gene.

Objective: To investigate the clinical phenotype and genetic diagnosis process of fetuses with 21 hydroxylase deficiency (21-OHD) caused by compound heterozygous variant of the CYP21A2 gene .

Methods: A fetus who was diagnosed at Taizhou Hospital in Zhejiang Province on December 4, 2020 due to unclear characteristics of external genitalia on ultrasound was selected as the study subject. Chromosome copy number variation sequencing (CNV-seq) and whole exome sequencing (WES) were performed on amniotic fluid samples. Candidate variants were validated by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA), and short tandem repeat (STR) analysis was used to exclude maternal blood contamination. The pathogenic mechanism of the variants was further explored. The procedure followed by this study was approved by the Medical Ethics Committee of Taizhou Hospital (Ethics No.: K20201009).

Results: The MRI examination of the fetal external genitalia showed thickening of labia minora and enlargement of the clitoris. The CNV-seq results of the fetus showed no significant abnormality. The WES results showed that the fetus had a homozygous c.293-13C>G variant in the CYP21A2 gene (NM-000500.9). STR testing excluded maternal blood contamination. Sanger sequencing verified the presence of heterozygous c.293-13C>G variant of the CYP21A2 gene in the fetus and its mother, while its father did not detect this mutation. Further MLPA testing results showed that the fetus and its father had heterozygous deletion (I2G-C locus) mutations in exon 1~7 of the CYP21A2 gene. Based on the "Standards and Guidelines for Interpretation of Sequence Variants" jointly developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), both variants of the CYP21A2 gene carried by the fetus were predicted to be pathogenic. According to the imaging and genetic testing results of the external genitalia of the fetus, the fetus was prenatally diagnosed as 21-OHD caused by the CYP21A2 gene variant. Follow-up after prenatal diagnosis showed that the couple had opted to terminate the pregnancy at a local hospital at 31⁺ weeks of gestation, and the clinical phenotype of the abortion fetus was consistent with the imaging and molecular genetic diagnosis.

Conclusion: The imaging features of this fetus are suspected to be congenital adrenal hyperplasia (CAH). Combined with WES, Sanger sequencing, and MLPA testing results, the fetus was diagnosed with 21-OHD caused by compound heterozygous variants of the CYP21A2 gene, which provided a basis for prenatal diagnosis.

Objective: To assess the clinical value of non-invasive prenatal testing (NIPT) for identifying maternal malignant tumors.

Methods: A retrospective analysis was carried out on pregnant women undergoing Non-invasive prenatal testing (NIPT) at Taizhou Hospital in Zhejiang Province from January 2018 to December 2022. The criteria included maternal copy number variations for at least two chromosomes. Clinical follow-up data were obtained for the high-risk population of maternal malignant tumors through telephone follow-up and review of electronic medical records. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: K20250339).

Results: Among 45 141 NIPT samples, 6 (0.013%) were suggested to have maternal malignant tumors. Follow-up information was available for 5 patients (83.3%). Two cases were diagnosed with maternal malignant tumors, including 1 myelodysplastic syndrome and 1 pelvic malignant tumor. Two cases were found to have multiple uterine fibroids and 1 was lost during follow-up.

Conclusion: The abnormal copy number indicated by NIPT may serve as an early signal for maternal malignant tumors. To establish a systematic follow-up protocol and multidisciplinary collaboration are conducive to achieving early diagnosis of tumors and improving the prognosis of patients. Based on the results of this study, it is recommended that for pregnant women with unexplained copy number variations and suspected maternal tumors by NIPT, targeted tumor screening program should be implemented to optimize their clinical management.

Objective: To explore the mechanism and clinical manifestations of a case with complex structural variations involving chromosomes 5, 7, and 14, and assess the value of Chromosome conformation-based karyotyping (C-MoKa) for its diagnosis.

Methods: Two half-sibs by the same father presented at the First Hospital of Lanzhou University in December 2024 for severe multi-system abnormalities were selected as study subjects. Peripheral blood samples from the their parents were subjected to conventional chromosomal karyotyping analysis. The father was further analyzed using C-MoKa, while both siblings underwent copy number variation sequencing (CNV-seq). This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: LDYYSZLLKH2025-05).

Results: Conventional karyotype analysis indicated that the father has a karyotype of 46,XY,add(5)(p15.3). CNV-seq identified multiple chromosomal abnormalities in both siblings, including duplications and deletions of chromosomes 14 and 5. C-MoKa analysis further revealed a complex chromosomal structural variation involving chromosomes 5, 7, and 14 in the father. These variations were closely associated with the severe phenotypes noted in both children.

Conclusion: Complex chromosomal structural variations can lead to multi-system abnormalities and significantly impact reproductive health. Compared to conventional karyotyping, the C-MoKa technique has shown significant advantage in identifying such complex rearrangements. The combined application of multiple techniques can improve the accuracy of diagnosis, enabling genetic counseling for carriers to reduce their risk for producing further affected offspring.

Objective: To analyze the clinical phenotype and genetic basis of four children with CHARGE syndrome.

Methods: A retrospective analysis was conducted on four children diagnosed with CHARGE syndrome at Xiamen Children's Hospital from May 2019 to May 2025. Peripheral venous blood samples were collected from the children and their parents and subjected to trio-whole exome sequencing. Candidate variants were verified by Sanger sequencing. Online tools were used for the conservation analysis and protein structure prediction. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2024-126).

Results: The four children have included two neonates, one infant and one child, with their age at the initial diagnosis ranging from 16 days after birth to 11 years old. Their initial manifestations were not typical of CHARGE syndrome. All children were found to harbor missense variants of the CHD7 gene, including c.3059T>C (p.L1020S), c.3302G>A (p.C1101Y), c.5879C>T (p.S1960F) and c.8093C>T (p.S2698L). Sanger sequencing confirmed that two were de novo variants, and two were inherited from their parents. In child 1, the leucine at position 1020 was highly conserved, and the p.L1020S variant did not alter the spatial structure and hydrogen bond connections of the CHD7 protein, though the shape of the binding cavity and the number and distribution of binding probe clusters have changed. In child 4, an unreported variant in the epilepsy gene SCN9A (c.2152T>C, p.Y718H) was detected, along with bilateral lower limb deformities. Literature review suggested that missense variants of the CHD7 gene were most common (32.1%) among the Chinese population, whilst nonsense variants had the highest lethality rate (41.2%) in neonates.

Conclusion: Variants of the CHD7 gene probably underlay the pathogenesis in the four children. Changes in the binding sites and binding cavity morphology play an important role in CHARGE syndrome. The types of genetic variants in CHARGE patients may vary between different regions and races.

Objective: To explore the clinical and genetic characteristics of a patient with Beck-Fahrner syndrome attributed to a TET3 gene variants.

Methods: A case of Beck-Fahrner syndrome (proband) who was treated at the Children's Hospital of Nanjing Medical University in December 2021 was selected as the study subject. Clinical data of the family were collected. Peripheral blood samples of the proband and his parents were collected, and genomic DNA was extracted for whole exome sequencing (WES). Candidate variants were verified in the family by Sanger sequencing. According to the "Classification Criteria and Guidelines for Genetic Variations" formulated by the American College of Medical Genetics and Genomics (hereinafter referred to as "ACMG guidelines"), the pathogenicity of the TET3 gene variant sites was rated. This study was approved by the Medical Ethics Committee of the Children's Hospital of Nanjing Medical University (Ethics No.: 202402022-1).

Results: The proband was a male, with a age of 9 months at the time of consultation. His clinical manifestations included decreased muscle tone, global developmental delay, long face, and open mouth. WES revealed that he has harbored a c.2811_c.2812insAGAC (p.T938fs*27) (NM_001287491) truncation variant in exon 7 of the TET3 gene. Sanger sequencing showed that neither of his parents has harbored the same variant. According to the ACMG guidelines, the variant was rated as pathogenic (PVS1+PS2+PM2_Supporting).

Conclusion: The TET3 gene c.2811_c.2812insAGAC variant probably underlay the pathogenesis of Beck-Fahrner syndrome in the proband. Above discovery has enriched the mutational spectrum of the TET3 gene and provided a reference for the diagnosis and treatment of this disease.