Expanding the phenotypic variability of
            <i>MORC2</i>
            gene mutations: From Charcot‐Marie‐Tooth disease to late‐onset pure motor neuropathy

Jacquier, Arnaud; Ribault, Shams; Mendes, Michel; Lacoste, Nicolas; Risson, Valérie; Carras, Julien; Latour, Philippe; Nadaj‐Pakleza, Aleksandra; Stojkovic, Tanya; Schaeffer, Laurent

doi:10.1002/humu.24445

Cited by 10 publications

(4 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A previously reported patient with an adult-onset PD-SMA carried a variant in the MORC2 gene. 18 One patient with an infantile-onset PD-SMA carried a homozygous pathogenic variant in the DNAJB2 gene (AR). The specific genetic variants can be seen in eTable 1 ( links.lww.com/NXG/A614 ).…”

Section: Resultsmentioning

confidence: 99%

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

et al. 2023

Self Cite

View full text Add to dashboard Cite

Background and ObjectivesSpinal muscular atrophy (SMA) is mainly caused by homozygousSMN1gene deletions on 5q13. Non-5q SMA patients’ series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders.MethodsDescription of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel.ResultsSeventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis:BICD2(n = 9),DYNC1H1(n = 7),TRPV4(n = 4),VCP,HSBP1,AR(n = 2),VRK1,DNAJB2,MORC2,ASAH1,HEXB, and unexpectedly,COL6A3(n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS.DiscussionNon-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. Nevertheless, there is an unmet need to cluster these patients to aid in the identification of new genes.

show abstract

Section: Resultsmentioning

confidence: 99%

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the past decade, progress in genome-wide association studies has identified several independent genetic loci of MORC2 for diseases. For instance, MORC2 mutations are associated with some disorders, 34 , 35 , 36 including Charcot-Marie-Tooth (CMT) disease, 37 , 38 , 39 , 40 , 41 spinal muscular atrophy, 24 , 42 , 43 and neurological disorders, 44 especially Charcot-Marie-Tooth disease type 2Z (CMT2Z), 38 , 45 thus allowing a better understanding of the genetic architecture of MORC2. Mounting evidence has shown that mutations in MORC2 may be strongly associated with the development of multiple cancers.…”

Section: Mutationmentioning

confidence: 99%

Oncogenic MORC2 in cancer development and beyond

et al. 2024

View full text Add to dashboard Cite

“…It was found to be highly expressed in human embryonic and adult neural tissues and dynamically regulated in the developing and mature murine nervous systems [ 13 ]. Functional assays have found that MORC2 variants affect neurone survival, apoptosis, neurite outgrowth, and abnormal axon morphology in keeping with the axonal neuropathy seen in patients with MORC2 -related disorders [ 13 , 14 ]. Furthermore, MORC2 may have a role in tumorigenesis, promoting the proliferation, invasion, and migration of glioma by inactivation of PTEN/PI3K/AKT signaling [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel Heterozygous De Novo MORC2 Missense Variant Causes an Early Onset and Severe Neurodevelopmental Disorder

Arbide,

Elkhateeb,

Goljan

et al. 2024

Case Reports in Genetics

View full text Add to dashboard Cite

Microrchidia CW-type zinc finger protein 2 (MORC2) is an ATPase-containing nuclear protein which regulates transcription through chromatin remodelling and epigenetic silencing. MORC2 may have a role in the development of neurones, and dominant variants in this gene have recently been linked with disorders including Charcot-Marie-Tooth type 2Z disease, spinal muscular atrophy and, more recently, a neurodevelopmental syndrome consisting of developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN), presenting with hypotonia, microcephaly, brain atrophy, intellectual disability, hearing loss, faltering growth, and craniofacial dysmorphism. Notably, variants in MORC2 have shown clinical features overlapping with those of Cockayne and Leigh syndromes. Here, we report a case of MORC2-related DIGFAN syndrome in a female infant caused by a novel heterozygous de novo variant. The condition was early onset and severe, further expanding the range of genotypes associated with this disorder. Clinical features included unilateral hearing loss, developmental delay and regression within the first year of life, microcephaly, severe feeding difficulties, and faltering growth, resulting in death at 13 months of age.

show abstract

Expanding the phenotypic variability of MORC2 gene mutations: From Charcot‐Marie‐Tooth disease to late‐onset pure motor neuropathy

Cited by 10 publications

References 29 publications

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

Oncogenic MORC2 in cancer development and beyond

A Novel Heterozygous De Novo MORC2 Missense Variant Causes an Early Onset and Severe Neurodevelopmental Disorder

Contact Info

Product

Resources

About