A Chinese pediatric patient with epilepsy and congenital heart disease who carries a novel CACNA1E variant that lies in a highly conserved and intolerant region provides a potential treatment clue for ACTH responsiveness in CACNA1E-related spasms.
Abstract
Background CACNA1E mutations cause developmental and epileptic encephalopathy. We report a Chinese pediatric patient with epilepsy and congenital heart disease who carries a novel CACNA1E variant. Methods Whole-exome sequencing (WES) was performed on the proband and his unaffected parents. The variant was validated by Sanger sequencing and screened in 200 healthy controls. Bioinformatic tools and ACMG criteria were used for pathogenicity assessment. Results A de novo heterozygous missense variant, NM_000721.4: c.1256G > A (p.R419Q), was identified. It was absent in both parents and in 200 controls. The variant lies in a highly conserved and intolerant region. ACMG classification: likely pathogenic (PS2 + PM2 + PP3). The patient showed marked short-term response to adrenocorticotropic hormone (ACTH). Conclusion This novel variant expands the mutational spectrum of CACNA1E and provides a potential treatment clue for ACTH responsiveness in CACNA1E-related spasms.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both upper and lower motor neurons, disturbing communication between the brain and muscles. So far, few reports have been published for the SPG11-associated ALS, and this is the first documented case from Pakistan. We report a rare subtype of ALS with an autosomal recessive mode of inheritance with juvenile onset before 25 years of age in the five affected individuals from two unrelated families. Whole-exome sequencing was performed to identify disease-causing variants, and selected variants were further prioritized based on predicted pathogenicity and similarity to clinical phenotypes. Two homozygous variants within the SPG11 gene were identified as pathogenic according to the ACMG and ClinGen Sequence Variant Interpretation (SVI) Working Group recommendations: a novel truncation (NM_025137.4:c.6738dup, p.Glu2247Ter) variant as validated by Sanger sequencing and a recurrent nonsense (NM_025137.4: c.782C>A, p.Ser261Ter) variant (rs765477482) previously reported in a family affected with autosomal recessive hereditary spastic paraplegia (ARHSP). In silico prediction tools further confirmed their pathogenicity. Five patients with juvenile-onset ALS born to consanguineous parents were found to have homozygous SPG11 gene variants. Our findings describe the overlapping phenotypes ofSPG11-related autosomal recessive juvenile ALS and ARHSP, suggesting that these disorders show a clear overlapping phenotype with common genetic defects. In clinical practice, it is challenging to distinguish between these two disorders. Additional Mendelian cases should be included to clarify further and investigate whether these represent two diverse diseases caused by variants in a single gene.
Riaz Ahmad, Muhammad Naeem, H. Houlden· Molecular Biology Reports· 0 citations
It is demonstrated that even in the absence of functional experiments, comprehensive family analysis can provide crucial clues for variant of uncertain significance (VUS) interpretation.
Xiulan Hao, Yanchou Ye, Man Liu et al.· Frontiers in Genetics· 0 citations
To investigate the novel genetic mutations and clinical characteristics in a patient with MYH9 related disease in order to enhance understanding of the disease. Clinical information was obtained, including medical history, pertinent laboratory tests, and family history. Whole exome sequencing (WES) was conducted on the patient and her parents. A 19-year-old female presented with a history of epistaxis and chronic thrombocytopenia. Her aunt and brother also have a history of thrombocytopenia. Sequencing analysis revealed mutations of MYH9 gene (c.5765 + 2T > G) and HBB gene (c.126_129del) in the patient, with the c.5765 + 2T > G mutation being previously unreported. The splice site mutation of MYH9 was predicted to be pathogenic by Mutation Taster and Polyphen software programs. As a result of identifying this splicing site mutation in this particular case, we have added c.5765 + 2T > G to the broad spectrum of potential MYH9 mutations.
Haocheng Li, Xiang Li, Wanlei Sun et al.· Annals of Hematology· 0 citations
A novel deletion variant in a Wilson disease patient harboring compound heterozygous variants in ATP7B is identified, expanding the known spectrum of pathogenic ATP7B variants.
Lipeng Yang, Jun Li, Si Xie et al.· Frontiers in Neurology· 0 citations
Background Autosomal dominant polycystic kidney disease (ADPKD) is most commonly caused by pathogenic variants in PKD1. Here, we reported the functional characterization of an intronic PKD1 variant identified in an ADPKD-affected family and its subsequent application in preimplantation genetic testing for monogenic disorders (PGT-M). Case presentation A three-generation ADPKD family was enrolled. Whole-exome sequencing revealed a heterozygous PKD1 c.7489 + 5G>A variant, which co-segregated with the disease and was initially classified as a variant of uncertain significance. A minigene assay demonstrated that the variant induced skipping of exon 18, leading to a frameshift (p.Arg2404Valfs*123), supporting its reclassification as pathogenic. The couple underwent PGT-M using trophectoderm biopsy, haplotype linkage analysis, and direct mutation detection. An unaffected pregnancy was achieved, and subsequent prenatal diagnosis confirmed the absence of the variant and a normal chromosomal karyotype. Conclusion We validated a pathogenic splicing variant in PKD1 and successfully applied PGT-M to prevent disease transmission, resulting in an unaffected pregnancy.
Qiong Pan, Yuefang Liu, Xueping Sun et al.· Frontiers in Genetics· 0 citations
A Chinese patient presenting with classic hallmarks of MGORS7 alongside atypical clinical features, including hearing and visual impairments is reported, suggesting that growth hormone therapy may be beneficial for growth retardation in patients with MGORS7.
Ying Zhao, Yiyang Fu, Shuying Zhang et al.· Frontiers in Genetics· 0 citations
