Jul 2026· Movement Disorders· 0 citations· 12 references
Medicine
TL;DR
This study supplemented the evidence on the role of PCDHGB1 in dystonia and expanded the genotypic and phenotypic spectrum of PCDHGB1.
Abstract
Background
Recently, PCDHGB1 has been identified as a novel causative gene of dystonia predominantly affecting the cervical muscles. However, no large cohort study has been conducted to confirm the association.
Objectives
The objective of the study was to systematically evaluate the genetic associations of PCDHGB1 with dystonia in a large Chinese dystonia cohort.
Methods
We analyzed rare variants of PCDHGB1 in a discovery cohort, including 878 dystonia patients, and a validation cohort, including 509 dystonia patients, using whole-exome sequencing. The overrepresentation of rare variants in patients was examined using Fisher's exact test at allele and gene levels.
Results
Twenty-seven rare variants of PCDHGB1 were identified in 55 individuals in the discovery cohort, including 3 frameshift variants (p.Leu177Valfs*7, p.Arg635Profs*24, p.Asp797Glufs*51) and 24 missense variants. Another 10 rare variants were detected in 12 patients in the validation cohort, including 1 frameshift variant (p.Leu709Argfs*13) and 9 missense variants. Fourteen patients carried the frameshift variant p.Leu177Valfs*7. Thirteen patients carried the p.Met111Val variant, including 3 patients from one family. At variant level, p.Pro773Ser and p.Arg408Gln were significantly associated with a higher risk of dystonia, whereas 15 variants (including p.Arg635Profs*24, p.Asp797Glufs*51, p.Leu709Argfs*13, and 12 missense variants) were nominally associated with a higher risk of dystonia. Gene-based burden analysis detected the enrichment of ultra-rare variants of PCDHGB1 in dystonia. Western blot experiments revealed that these four frameshift variants (p.Leu177Valfs*7, p.Arg635Profs*24, p.Asp797Glufs*51, p.Leu709Argfs*13) induced a truncated PCDHGB1 protein.
This study identifies novel loss-of-function RSPH4A variants causing PCD through distinct molecular mechanisms, expanding the mutational spectrum of radial spoke head protein-related ciliopathies.
Yuting Lu, Hui-Yan Tang, Kai Chen et al.· Frontiers in Genetics· 0 citations
BACKGROUND
Pathogenic missense variants in the MORC2 gene are associated with two distinct disorders: Charcot-Marie-Tooth disease type 2Z (CMT2Z) and the recently described DIGFAN (developmental delay, impaired growth, dysmorphic facies and axonal neuropathy) phenotype, which encompasses a broad range of clinical manifestations that vary significantly between individuals.
METHODS
Clinical and imaging data from 16 patients were collected. Western blot analysis was performed on 10 identified variants in affected patients as well as on two novel variants without clinical data. Those missense variants were introduced into the wild-type vector transfected into HEK293T cells, and western blot analysis was performed to assess protein expression level.
RESULTS
A total of 11 different missense variants in the MORC2 gene were identified in our cohort, including four novel variants. We demonstrate that early-onset MORC2-associated disorders segregate into two principal neurological phenotypes: a predominantly neuromuscular form and a central nervous system-predominant form. The p.Ser87Leu variant, which defines the neuromuscular cluster, was uniquely characterised by a significant reduction in MORC2 protein levels, distinguishing it mechanistically from other variants. Overall, western blot analysis revealed no statistically significant difference in protein expression levels between variants related to CMT2Z and DIGFAN cases.
CONCLUSION
A comparison of our patients with previously reported cases revealed an intriguing trend suggesting a probable dependence of the leading clinical features on specific variants in the MORC2 gene. Further accumulation of patient data is required to determine whether this observation correlates with other specific variants.
A. Murtazina, Eugenii Tatarsky, I. Viakhireva et al.· Journal of Medical Genetics· 0 citations
BACKGROUND
Variants in GBA1 are associated with neurodegenerative disease. This study aimed to explore pathogenic GBA1 variants.
METHODS
Four patients with progressive myoclonic epilepsy (PME) and extremely low β-glucosidase levels were recruited. Whole-exome sequencing and long-range PCR were performed to identify GBA1 variants. Bioinformatic analyses were used to predict the impact of the identified variants. A literature review was performed to explore the genotype-phenotype correlations. GBA1 expression data across different brain regions and developmental stages were analyzed using the BrainSpan database. RT-PCR was performed to verify the splicing effects.
RESULTS
Compound heterozygous GBA1 variants were identified in four patients. Five distinct variants were detected, including two novel splice site variants (c.308-2A>G and c.762-2A>C) and three previously reported variants. All identified variants were rare or absent in gnomAD. Splice site variants c.308-2A>G and c.762-2A>C were predicted to cause aberrant splicing. Minigene-based splicing assays coupled with RT-PCR and Sanger sequencing confirmed that both variants cause complete exon skipping (exon 4 and exon 7, respectively). All patients presented with PME onset in childhood/adolescence, intellectual regression, low β-glucosidase, and diffuse brain atrophy and were subsequently diagnosed with Gaucher disease type 3. GBA1 expression in the brain showed two distinct peaks: one in infancy and another after five years of age. The onset age of PME aligned with the second GBA1 expression peak (after five years of age).
CONCLUSION
This study identified compound heterozygous GBA1 variants, including two novel candidate pathogenic splice site variants, in Gaucher disease type 3 patients, expanding the known mutational spectrum.
Yang-Mei Ou, Ming-Feng He, Fu-Jiang Yan et al.· Brain & development (Tokyo....· 0 citations
OBJECTIVES
Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is a rare disorder caused by biallelic mutations in ACP5. This study systematically evaluates genetic landscape, clinical features, treatment, and transcriptomics in SPENCDI.
METHODS
Whole-exome sequencing was performed for genetic diagnosis of patients from multiple centers, and tartrate-resistant acid phosphatase (TRAP) activity was measured for novel variants. Previously reported cases were integrated with the current cohort for analysis of genotypes, clinical characteristics, laboratory findings, and treatment responses. Bulk and single-cell RNA sequencing investigated immune signaling alterations.
RESULTS
We identified 17 patients with ACP5 deficiency from Egypt and China, discovering five novel pathogenic variants (A260D, L257P, G32D, K190Nfs*22, and T305Nfs*12). Three novel missense variants were detected with loss of TRAP activity. Clinical manifestations involve multiple systems, with the skeletal system most frequently involved (32.31%), where skeletal dysplasia (94.32%) and short stature (81.82%) are the predominant features. Patients showed elevated inflammatory activity, with enrichment of the NF-κB, MAPK, and cell death pathways, as well as upregulation of type I interferon genes in monocytes. Enhanced IFN-γ signaling interactions between monocytes and Natural Killer cells were observed. Therapeutically, Prednisolone and Azathioprine were the most common effective drugs, while patients treated with the Janus kinase inhibitors Ruxolitinib or Upadacitinib achieved a partial response.
CONCLUSIONS
This study expanded the genetic and clinical spectrum of ACP5 deficiency. An upregulated interferon signature was revealed, and monocytes were identified as a major cellular source of inflammation. These results provide valuable insights for improving the diagnosis and treatment of SPENCDI.
Shiling Zhong, Shuangyue Ma, Yasmine El Chazli et al.· Arthritis & Rheumatology· 0 citations
A novel missense variant is characterized that causes aberrant splicing of PKHD1 in CD and underscores the necessity of functional analysis for evaluating the pathogenicity of missense variants, especially those at the last nucleotide of an exon.
In this study, pathogenic FBN1 variants were identified in three patients, thereby confirming the clinical diagnosis of MFS and contributing two novel variants to the FBN1 variant repository, and provide a comparative assessment of genotype-phenotype correlations.
Xing Zhao, L. Yuan, Yan Sun et al.· Clinica chimica acta; intern...· 0 citations
