Jul 2026· Movement Disorders· 0 citations· 43 references
Medicine
TL;DR
Downstream regulatory variants are a substantial cause of NKX2-1-RDs and diagnostic strategies should include this regulatory region and systematic structural variant detection, particularly when coding variants have been excluded.
Abstract
Background
NKX2-1-related disorders (NKX2-1-RDs) classically present with a triad of neurological, endocrine, and pulmonary manifestations, including benign hereditary chorea. However, in a fraction of patients, NKX2-1 coding variants are not detected, and variants outside the NKX2-1 locus have been reported.
Objective
The objective of this study was to evaluate the clinical spectrum and frequency of regulatory variants in NKX2-1-RDs.
Methods
Eight families carrying structural variants near NKX2-1 without disruption of the coding sequence were recruited, and clinical data were systematically collected. Regulatory activity was assessed using EpiMap data. Frequency and diagnostic yield were evaluated in a cohort of 26 individuals with molecularly confirmed NKX2-1-RD.
Results
Eight families comprising 13 affected individuals were identified: five with downstream deletions and three with complex structural rearrangements. Neurological manifestations were universal, including chorea, myoclonus, and ataxia, while cognitive or behavioral abnormalities occurred in a subset. Individuals with deletions rarely presented extraneurological features, whereas all carriers of complex structural variants showed the complete triad. All deletions and breakpoints were located downstream of NKX2-1. The core shared deleted region showed open chromatin and H3K27ac peaks in fetal brain, lung, and thyroid tissues, suggesting regulatory activity. Regulatory variants accounted for 27% of NKX2-1-RD diagnoses in our institutions. Exome sequencing combined with copy-number variant analysis captured 92% of diagnoses when MBIP was evaluated as a target for downstream variants.
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
The findings suggest that PPP1R12A-related disorders may exhibit a broader phenotypic variability than previously recognized and it is proposed that HL and inner ear malformations may represent novel features associated with this clinical spectrum.
G. Pianigiani, Lara Emily Rosso, Anna Morgan et al.· Genes· 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
Heterotaxy (HTX) is a rare condition characterized by complex congenital heart defects and a wide spectrum of extracardiac abnormalities that significantly impact survival. While molecular diagnosis is essential for clinical management, next-generation sequencing (NGS) currently identifies disease-causing variants in only 20%-30% of HTX cases. To address this diagnostic gap, we collected cases of HTX investigated by trio-based whole-exome (WES) and whole-genome sequencing (WGS) and performed detailed clinical and molecular characterization in seven children and fetuses from France and Vietnam. In parallel, we conducted a systematic review of 108 published cases to refine genotype-phenotype correlations. We identified seven variants in four key genes: DNAH9, PKD1L1, MMP21, and GDF1. The findings revealed significant phenotypic heterogeneity while highlighting strong genotype-phenotype correlations, such as the association of MMP21 and GDF1 variants with severe conotruncal malformations. Two unreported variants were identified, further expanding the mutational spectrum of laterality defects. By integrating fetopathological data with advanced genomic analyses, we further delineate the phenotypic spectrum of these conditions. Ultimately, this work underscores the high diagnostic value of NGS in prenatal and neonatal cardiology, enabling earlier diagnosis and more personalized clinical management.
Thi Bich Tuyen Ho, Alicia Coudert, Thi Thuy Hang Do et al.· Clinical 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
Purpose: Neurofibromatosis type 2-related schwannomatosis (NF2-SWN) is an autosomal dominant tumor syndrome with complete penetrance and variable expressivity. Underlying patterns of disease burden and severity are largely unexplained. Methods: We comprehensively phenotyped 168 NF2-SWN patients over a mean duration of 4.5 years. We used a custom sequencing panel of NF2 and schwannomatosis genes to identify germline (n=166) and somatic variants in tumors (n=37). An optimized composite severity (CSS) score based on clinical and radiological data was created to analyze the effect of genetic variants on phenotype. Results: We found significant variable expressivity not explainable by demographic variables. Germline variants included premature termination (42%), splice-site (18%), and large deletions (16%). The CSS successfully predicted worsening clinical function in patients. Unsupervised clustering of clinical data revealed distinct phenotypic clusters that corresponded to CSS. Mosaicism, however, was not associated with CSS or any other disease severity marker. CSS was significantly associated with germline variant location along the NF2 locus. Specifically, FERM-F1 and the -helical variants were associated with increased disease severity. Within tumors, germline variants with severe effects on merlin acquired milder somatic second-hits at the NF2 locus. Conclusion: We identified a second-hit modifier to the Mendelian first-hit: severe germline variants were associated with milder somatic variants, and vice versa. This phenomenon partly explains the variable expressivity in NF2-SWN.
N. Ravindra, David T. Asuzu, Emma C. Celano et al.· medRxiv· 0 citations