中华医学遗传学杂志最新文献

Objective: To explore the clinical phenotypes and genetic characteristics of a Chinese pedigree affected with X-linked Charcot-Marie-Tooth disease (CMTX) with childhood-onset episodic encephalopathy as the initial manifestation.

Methods: Clinical data and auxiliary examination results of a pedigree with "limb weakness, dysarthria and dysphonia" presented at the Affiliated Hospital of Guangdong Medical University between April 2023 and December 2024 were retrospectively analyzed. The proband and other pedigree members underwent whole exome sequencing. Candidate variants were subsequently validated within the pedigree by Sanger sequencing. In addition, literature search and summary analysis were carried out using keywords including "X-linked Charcot-Marie-Tooth disease type 1," "children," and "GJB1 gene" in the China National Knowledge Infrastructure, WanFang Data Knowledge Service Platform, and PubMed databases. This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Guangdong Medical University (Ethics No.: YJYS2022352).

Results: The pedigree has comprised five affected individuals from three generations. The probands were monozygotic male twins with the onset age of 10 and 11 years, respectively, without preceding infection. Both child had presented with limb weakness, dysarthria, and dysphonia as initial symptoms, which were improved with treatment. Brain MRI revealed bilateral frontoparietal white matter lesions. Electromyography demonstrated peripheral neuropathy in the four limbs. Whole exome sequencing identified a c.224G>A (p.Arg75Gln) missense variant in the GJB1 gene, which was inherited from the mother. The variant was classified as pathogenic based on the guidelines from American College of Medical Genetics and Genomics (ACMG) (PS3+PS4+PM2_Supporting+PM5+PP3), confirming the diagnosis of CMTX1. No symptom has occurred during the follow-up, and repeat brain MRI one year post-onset showed complete resolution of the abnormalities. Literature review has identified 18 male pediatric CMTX1 cases presenting with encephalopathy as the initial manifestation. Episodic limb weakness, dysarthria, and facial palsy were the main clinical manifestations. MRI predominantly showed transient hyperintense signals in the periventricular deep white matter, centrum semiovale, and splenium of corpus callosum, which resolved spontaneously within weeks to months.

Conclusion: For male pediatric patients presenting with episodic encephalopathy, peripheral neuropathy, and transient white matter abnormalities on brain MRI, CMTX1 should be suspected. Early implementation of neurophysiological studies and GJB1 gene testing is crucial for timely diagnosis, precise management, and accurate genetic counseling.

Objective: To explore the clinical phenotypes and genetic characteristics of two patients with Familial adenomatous polyposis (FAP) due to variants of MUTYH gene.

Methods: Two patients presenting with multiple colorectal polyps on gastrointestinal endoscopy at Xinxiang Central Hospital respectively in June and October 2022 were selected as study subjects. A retrospective study design was employed to collect their clinical data and summarize their clinical and genetic features. Whole exome sequencing (WES) was carried out for both patients. Candidate variants were validated by Sanger sequencing of their family members. Bioinformatic analysis was conducted for the candidate variants. Pathogenicity of the variants was assessed based on the guidelines from American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the hospital [Ethics No.: 2024-282-01 (K)].

Results: Patient 1 was a 7-year-old girl who presented with "pigmentation on the lips, buccal mucosa, hard palate, eyelids and fingers for 5 years." Colonoscopy revealed multiple colonic polyps. WES revealed that she has harbored compound heterozygous variants of the MUTYH gene, namely c.857G>A (p.Gly286Glu) and c.1118C>T (p.Ala373Val), which were inherited from her mother and father, respectively. Based on the ACMG guidelines, the variants were classified as pathogenic (PS4+PM1+PM2_Supporting+PP3) and variant of uncertain significance (VUS) (PM2_Supporting+PP3), respectively. Patient 2 was a 42-year-old male who presented with "increased frequency of bowel movements for 2 month." Colonoscopy revealed multiple colorectal polyps. WES revealed that he has harbored compound heterozygous variants of the MUTYH gene, namely c.53C>T (p.Pro18Leu) and c.880C>T (p.Arg294Cys), which were inherited from his father and mother, respectively. Based on the ACMG guidelines, the variants were classified as likely pathogenic (PS4+PM1+PM2_Supporting+PP3) and VUS (PM2_Supporting+PM1), respectively.

Conclusion: Compound heterozygous variants of the MUTYH gene probably underlay the pathogenesis of FAP in these patients. Above findings have enriched the mutational spectrum of the MUTYH gene.

Objective: To explore the clinical phenotype and genetic characteristics of a child with Coffin-Siris syndrome type 8 (CSS8) due to an intronic variant of the SMARCC2 gene.

Methods: A child who had attended the Women and Children's Hospital of Ningbo University on 5 March, 2025 was selected as study subject. Clinical data of the child was collected. Peripheral blood samples were collected from the child and her family members. Following extraction of genomic DNA, whole exome sequencing (WES) was carried out. Candidate variants was validated by Sanger sequencing. The effect of candidate variants on mRNA was analyzed using an in vitro minigene assay. CSS8-related publications were searched in home and oversea databases for a literature review. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: EC2023-094).

Results: The child had manifested intellectual disability, delayed language development, recurrent fever, rash, joint pain, and chronic multifocal aseptic osteomyelitis. WES revealed that she has harbored a heterozygous c.1496+2T>C variant of the SMARCC2 gene, which may affect the splicing of mRNA. Sanger sequencing verified that neither of her parents has carried the same variant. In vitro minigene assay indicated that the variant can affect the normal splicing of SMARCC2 mRNA and result in two abnormal transcripts including retaining of 126 bp upstream of intron 16 and skipping of exon 16. Both splicing forms did not alter the reading frame, but resulted in production of truncated proteins. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PS2_Moderate+PVS1_Moderate+PM2_Supporting+PS1_Supporting). The child was treated with naproxen and adalimumab, though she still had repeated episodes of attacks. After hormone supplementation and methotrexate treatment, her condition was relieved.

Conclusion: The c.1496+2T>C variant of the SMARCC2 gene probably underlay the pathogenesis of CSS8 in this child. Above finding has enriched the mutational and phenotypic spectra of the SMARCC2 gene.

Objective: To explore the genetic etiology of 210 Chinese pedigrees affected with Hemophilia and provide prenatal diagnosis and preimplantation genetic testing (PGT) for them.

Methods: A total of 210 unrelated pedigrees diagnosed with Hemophilia (176 with Hemophilia A and 34 with Hemophilia B) at the Reproductive and Genetic Hospital of CITIC-Xiangya between 2011 and 2024 were selected as study subjects. Genetic testing was carried out on the probands, including whole-exome sequencing, PCR-Sanger sequencing, and detection of intron 22 and intron 1 inversions of the F8 gene. Pathogenicity of candidate variants was classified based on the guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). After the determination of genetic causes, reproductive intervention was implemented through prenatal diagnosis or preimplantation genetic testing (PGT). This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010).

Results: In total 137 pathogenic or likely pathogenic variants of the F8 and F9 genes were identified among 207 pedigrees (detection rate = 98.5%), among which 16 were were unreported previously. Respectively, 105 pathogenic or likely pathogenic variants (including 13 novel ones) of the F8 gene were detected among 174 pedigrees with Hemophilia A, while 32 pathogenic or likely pathogenic variants (including 3 novel ones) of the F9 gene were identified among 33 pedigrees with Hemophilia B. Among the 207 pedigrees, 65 had opted for prenatal diagnosis, and 9 fetuses were diagnosed with Hemophilia, and the pregnancies were terminated. On the other hand, 71 pedigrees had opted PGT, with 454 embryos from 90 cycles completed testing, which yielded a diagnostic rate of 99.8% (453/454). As a result, 100 healthy infants were born through reproductive intervention.

Conclusion: This study has clarified the genetic basis of 207 pedigrees affected with Hemophilia. The results had expanded the mutational spectrum, and reduced the birth rate of Hemophilia by prenatal diagnosis and PGT.

Objective: To explore the clinical, genetic, treatment and prognostic characteristics of progressive familial intrahepatic cholestasis type 5 (PFIC5).

Methods: A retrospective analysis was carried out on the clinical data of a child diagnosed with PFIC5 at the Children's Hospital Affiliated to Zhengzhou University in June 2022. Peripheral blood samples from the child and his parents were collected, and trio-whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing and subjected to pathogenicity analysis. A literature search was conducted on various databases to identify previous reports on PFIC5-related cases due to variants of NR1H4 gene. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2023-H-H02).

Results: The child, a 3-month-and-4-day-old boy, presented with persistent jaundice onset from the neonatal period, elevated transaminases and bile acids, while his gamma-glutamyl transferase (GGT) remained normal. Genetic testing revealed that he has harbored c.925C>G (p.L309V) and c.1012G>A (p.E338K) compound heterozygous variants of the NR1H4 gene. Neither of the variants were reported previously. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), both variants were classified as likely pathogenic (PM2_Supporting+PP1+PP2+PP3+PP4; PM2_Supporting+PP1+PM5+PP4). Literature search has identified 1 Chinese and 7 English reports on NR1H4 variant-induced PFIC5, totaling 15 cases including the present one, including 7 cases from China. The age of onset has ranged from 1 day to 16 months, with a median age of 1 week. Typical clinical manifestations have included onset of progressive cholestasis from the neonatal period, elevated transaminases and alpha-fetoprotein, normal GGT, accompanied by hepatosplenomegaly and coagulopathy, which could rapidly progress to end-stage liver disease. Genetic testing is the main diagnostic method. Seven children (46.67%) had undergone liver transplantation. During a follow-up of 1 to 8 years, 6 cases had achieved symptom resolution, while 1 case had deceased 1 year after the transplantation. Of the 8 non-transplanted patients (53.33%, 8/15), 1 had an unknown prognosis and 7 had deceased. Survival rates had differed significantly between the transplantation group and non-transplantation group (Fisher's exact test, P = 0.005).

Conclusion: The c.925C>G (p.L309V) and c.1012G>A (p.E338K) compound heterozygous variants of the NR1H4 gene probably underlay the pathogenesis of PFIC5 in this child. For children with early-onset, refractory cholestasis and normal GGT, PFIC5 should be suspected, and genetic testing should be performed to facilitate early diagnosis and treatment.

Objective: To analyze the clinical characteristics and causative variation sites in a pedigree with hereditary coagulation factor Ⅴ (FⅤ) deficiency.

Methods: A pedigree with hereditary FⅤ deficiency who visited Xijing Hospital on March 2, 2025, was selected as the study subject. Clinical data of the pedigree were collected using a retrospective analysis method. Venous blood samples were collected from the proband and family members to obtain platelet-poor plasma and genomic DNA. FⅤ activity (FⅤ:C) was measured by coagulation assay, and FⅤ antigen (FⅤ:Ag) was measured by ELISA for all members. Sanger sequencing was used to detect all exons and flanking sequences of the F5 gene in all members to screen for variations. Thrombin generation assay was performed to evaluate the overall coagulation potential of the proband and parents. Multiple online software tools, including ClustalX-2.1-win, PolyPhen-2, PROVEAN, I-Mutant v2.0, SIFT, Mutation Taster, and Swiss-Pdb Viewer, were used to assess the conservation of the variation sites and their impact on protein structure and function. The pathogenicity of the variation sites was evaluated according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for the interpretation of sequence variants. This study was approved by the Medical Ethics Committee of Xijing Hospital (Ethics No.: KY20252367).

Results: The proband's FⅤ:C level was only 1.3%, and the FⅤ:Ag level was only 2.4%. The proband was found to carry the c.653T>C (p.Phe218Ser) variant in exon 5 and the c.5660A>T (p.Glu1887Val) variant in exon 18 of the F5 gene. According to the ACMG guidelines, these two variants were classified as "Pathogenic" (PS4+PM2_Supporting+PP1+PP3+PP4+PP5) and "Likely Pathogenic" (PM1+PM2_Supporting+PM3+PP1+PP2+PP3+PP4), respectively. The proband's father and grandfather carried the p.Phe218Ser variant in heterozygous state, and the mother and maternal grandmother carried the p.Glu1887Val variant in heterozygous state. The paternal grandmother and maternal grandfather were wild-type. Thrombin generation assay showed delayed thrombin generation and reduced thrombin output in the proband and parents, indicating impaired coagulation function. Bioinformatics analysis revealed that Phe218 and Glu1887 are highly conserved. Both the p.Phe218Ser and p.Glu1887Val variants were predicted to be deleterious, potentially disrupting local protein conformation and stability, which may lead to functional defects.

Conclusion: The compound heterozygous variants p.Phe218Ser and p.Glu1887Val may cause a significant decrease in FⅤ:C and FⅤ:Ag by disrupting the structure and function of the FⅤ protein.

Objective: To assess the susceptibility to seizures, expression of fibroblast growth factor 17 (Fgf17) in rats with Cortical dysplasia (CD), and its effect on hippocampal neurons.

Methods: Pregnant SPF SD rats were intraperitoneally injected with Carmustine on E17 to establish a model of CD in the offspring rats. The offspring were randomly divided into the normal control, epilepsy group, CD group, and CD plus epilepsy group (n = 20 each). At 6 weeks of age, the rats from the epilepsy and CD plus epilepsy group were intraperitoneally injected with lithium chloride and pilocarpine to induce status epilepticus (SE). Quantitative real-time PCR and Western blotting were used to detect the mRNA and protein levels of Fgf17 at 24 hours and 30 days post-SE, respectively. An electrophysiological signal system was used to record the firing rate, amplitude, and seizure duration of the electroencephalogram (EEG) in rats from the 4 groups at 30 days post-SE. According to the concentration of Fgf17 in the culture medium, 12 1-day-old rats were divided into the control group, 500 nmol/L Fgf17 group, and 1 000 nmol/L Fgf17 group (n = 4 each). Immunofluorescence staining was used to observe the morphometry and number of hippocampal neurons in the 3 groups. This study was approved by the Ethics Committee of the Fifth Affiliated Hospital of Zhengzhou University (Ethics No.: KY2023005).

Results: Hematoxylin-Eosin (HE) staining indicated CD in rats from the CD group and CD plus epilepsy group. Compared with the epilepsy group, the CD plus epilepsy group exhibited a faster rate of seizure onset, higher EEG amplitudes, and longer seizure at 30 days post-SE (P < 0.05). Both the CD and the CD plus epilepsy groups showed lower mRNA and protein expressions of Fgf17 in the hippocampus at 24 hours and 30 days post-SE compared with the control and epilepsy groups (P < 0.05), with the expression significantly decreased in the CD plus epilepsy group. Both the 500 nmol/L and the 1 000 nmol/L Fgf17 groups showed a greater number of hippocampal neurons compared with the control group (P < 0.05). The number of hippocampal neurons in the 1 000 nmol/L Fgf17 group was significantly greater compared with the 500 nmol/L Fgf17 group (P < 0.05).

Conclusion: Rats with CD exhibit decreased Fgf17 expression and increased epileptogenic susceptibility, which may be associated with reduced number of hippocampal neurons.

Objective: To investigate the genetic etiology of two pediatric patients presenting with developmental delay and microcephaly.

Methods: Two patients diagnosed with developmental delay and microcephaly at the Children's Hospital of Nanjing Medical University in February 2023 and March 2024 were enrolled. Peripheral blood samples were collected from both children and their parents. Genomic DNA was extracted and subjected to whole exome sequencing (WES). Suspected variants were verified by Sanger sequencing. Pathogenicity of the identified variants was assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Structural visualization of the variant proteins was performed using PyMOL software. A literature review was conducted to summarize reports on PCDH12 gene variants associated with Diencephalic-mesencephalic junction dysplasia syndrome type 1 (DMJDS1). This study was approved by the Medical Ethics Committee of Children's Hospital of Nanjing Medical University (Ethics No.: 202402022-1).

Results: Patient 1 was a 5-year and 9-month-old female with congenital microcephaly, global developmental delay, distinctive facial features, intellectual disability, gait instability, and ataxia. Brain MRI indicated cerebral dysgenesis. WES revealed compound heterozygous PCDH12 variants: paternal c.522_525delGTCT (p.S175Pfs*22) and maternal c.244G>T (p.E82*). Both variants were classified as pathogenic according to ACMG guidelines. Patient 2 was a 7-day-old male. Prenatal ultrasound showed microcephaly, and fetal MRI revealed a thin corpus callosum. Postnatally, he exhibited primary microcephaly, global developmental delay, and brain MRI findings included widened lateral ventricles, thin corpus callosum, and abnormal morphology of the bilateral cerebral peduncles. WES identified compound heterozygous PCDH12 variants: maternal c.522_525delGTCT (p.S175Pfs*22) and paternal c.466delC (p.L156Wfs*42). The c.466delC variant was classified as pathogenic. Based on the clinical phenotypes and genetic findings, both patients were diagnosed with DMJDS1. PyMOL analysis indicated that all three PCDH12 variants result in protein truncation. A review of 12 published articles identified 44 reported DMJDS1 cases (including the 2 cases in this study) associated with 19 distinct PCDH12 variants, of which only one previous case involved compound heterozygosity; all others were homozygous.

Conclusion: Compound heterozygous variants in the PCDH12 gene are likely the genetic cause of microcephaly and developmental delay in these two patients. The c.244G>T and c.466delC variants are novel, thereby expanding the mutational spectrum of the PCDH12 gene.

Objective: To investigate the clinical features and genetic etiology of a patient with Alström syndrome (ALMS) who presented with paroxysmal palpitations.

Methods: Clinical data were collected from a 20-year-old female patient who was admitted to Fuwai Hospital, Chinese Academy of Medical Sciences in April 2024. Her medical history was obtained, and physical examination, auxiliary investigations, and laboratory tests were carried out. Peripheral blood samples were collected from the patient and her parents. Whole-exome sequencing (WES) was performed, followed by bioinformatic analysis to identify candidate variants. Pathogenicity assessment was conducted based on the guidelines from American College of Medical Genetics and Genomics (ACMG). Sanger sequencing was subsequently conducted for the patient and her parents to confirm the presence of the variants and determine their parental origin. The study was approved by the Ethics Committee of the institution (Ethics No.: 2026-3045).

Results: The patient exhibited multisystem involvement including paroxysmal atrial flutter, retinitis pigmentosa, type 2 diabetes mellitus, and hypothyroidism. Electrophysiological examination confirmed right atrial isthmus-dependent atrial flutter. The patient underwent successful radiofrequency ablation. WES revealed that she has harbored heterozygous c.9472C>T (p.Lys579GlufsTer17) and c.1734dup (p.Gln3158Ter) variants of the ALMS1 gene. Bioinformatic analysis suggested that both variants can result in significant alteration in the protein. Pathogenicity analysis showed that both variants were unrecorded in the population and disease-related databases and have loss-of-function effects. Based on the ACMG guidelines, both variants were classified as likely pathogenic. Sanger sequencing confirmed that the two variants were inherited from different parents, constituting compound heterozygous variants. The possible mechanisms underlying the patient's clinical manifestations and recent advances in ALMS research were also summarized.

Conclusion: Compound heterozygous ALMS1 variants c.9472C>T and c.1734dup probably underlay the pathogenesis of ALMS in this patient. Above findings have expanded the genotype-phenotype spectrum of ALMS and facilitated understanding of its genetic basis, pathogenic mechanism, and clinical manifestations, thereby promoting early diagnosis and standardized management.