Further evidence for POMK as candidate gene for WWS with meningoencephalocele

Abstract Background Walker-Warburg syndrome (WWS) is a rare form of alpha-dystroglycanopathy characterized by muscular dystrophy and severe malformations of the CNS and eyes. Bi-allelic pathogenic variants in POMK are the cause of a broad spectrum of alpha-dystroglycanopathies. POMK encodes protein-O-mannose kinase, which is required for proper glycosylation and function of the dystroglycan complex and is crucial for extracellular matrix composition. Results Here, we report on male monozygotic twins with severe CNS malformations (hydrocephalus, cortical malformation, hypoplastic cerebellum, and most prominently occipital meningocele), eye malformations and highly elevated creatine kinase, indicating the clinical diagnosis of a congenital muscular dystrophy (alpha-dystroglycanopathy). Both twins were found to harbor a homozygous nonsense mutation c.640C>T, p.214* in POMK, confirming the clinical diagnosis and supporting the concept that POMK mutations can be causative of WWS. Conclusion Our combined data suggest a more important role for POMK in the pathogenesis of meningoencephalocele. Only eight different pathogenic POMK variants have been published so far, detected in eight families; only five showed the severe WWS phenotype, suggesting that POMK-associated WWS is an extremely rare disease. We expand the phenotypic and mutational spectrum of POMK-associated WWS and provide evidence of the broad phenotypic variability of POMK-associated disease.

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Novel LAMA2 variants identified in a patient with white matter abnormalities

Human Genome Variation ◽

10.1038/s41439-020-0103-5 ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Keiko Yamamoto-Shimojima ◽

Hiroaki Ono ◽

Taichi Imaizumi ◽

Toshiyuki Yamamoto

Keyword(s):

Creatine Kinase ◽

White Matter ◽

Muscular Dystrophy ◽

Developmental Delay ◽

Congenital Muscular Dystrophy ◽

Genomic Analysis ◽

Compound Heterozygous ◽

Loss Of Function ◽

White Matter Abnormalities ◽

Pathogenic Variants

AbstractComprehensive genomic analysis was performed in a patient with mild psychomotor developmental delay, elevated creatine kinase, and white matter abnormalities. The results revealed biallelic pathogenic variants in the gene related to merosin-deficient congenital muscular dystrophy, NM_000426.3(LAMA2):c.1338_1339del [p.Gly447Phefs*7] and c.2749 + 2dup, which consist of compound heterozygous involvement with predicted loss-of-function and splicing abnormalities.

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Natural history and genetic study of LAMA2-related muscular dystrophy in a large Chinese cohort

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01950-x ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Dandan Tan ◽

Lin Ge ◽

Yanbin Fan ◽

Xingzhi Chang ◽

Shuang Wang ◽

...

Keyword(s):

Muscular Dystrophy ◽

Natural History ◽

Copy Number ◽

Congenital Muscular Dystrophy ◽

Severe Pneumonia ◽

Copy Number Variations ◽

Chinese Patients ◽

Rapid Progression ◽

Mild Phenotype ◽

Pathogenic Variants

Abstract Background LAMA2-related muscular dystrophy including LAMA2-related congenital muscular dystrophy (LAMA2-CMD) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by LAMA2 pathogenic variants. We aimed to describe the natural history and establish genotype–phenotype correlations in a large cohort of Chinese patients with LAMA2-related muscular dystrophy. Methods Clinical and genetic data of LAMA2-related muscular dystrophy patients enrolled from ten research centers between January 2003 and March 2021 were collected and analyzed. Results One hundred and thirty patients (116 LAMA2-CMD and 14 LGMDR23) were included. LAMA2-CMD group had earlier onset than LGMDR23 group. Head control, independent sitting and ambulation were achieved in 76.3%, 92.6% and 18.4% of LAMA2-CMD patients at median ages of 6.0 months (range 2.0–36.0 months), 11.0 months (range 6.0–36.0 months), and 27.0 months (range 18.0–84.0 months), respectively. All LGMDR23 patients achieved independent ambulation at median age of 18.0 months (range 13.0–20.0 months). Motor regression in LAMA2-CMD mainly occurred concurrently with rapid progression of contractures during 6–9 years old. Twenty-four LAMA2-related muscular dystrophy patients died, mostly due to severe pneumonia. Seizures occurred in 35.7% of LGMDR23 and 9.5% of LAMA2-CMD patients. Forty-six novel and 97 known LAMA2 disease-causing variants were identified. The top three high-frequency disease-causing variants in Han Chinese patients were c.7147C > T (p.R2383*), exon 4 deletion, and c.5156_5159del (p.K1719Rfs*5). In LAMA2-CMD, splicing variants tended to be associated with a relatively mild phenotype. Nonsense variants were more frequent in LAMA2-CMD (56.9%, 66/116) than in LGMDR23 (21.4%, 3/14), while missense disease-causing variants were more frequent in LGMDR23 (71.4%, 10/14) than in LAMA2-CMD (12.9%, 15/116). Copy number variations were identified in 26.4% of survivors and 50.0% of nonsurvivors, suggesting that copy number variations were associated with lower rate of survival (p = 0.029). Conclusions This study provides better understandings of natural history and genotype–phenotype correlations in LAMA2-related muscular dystrophy, and supports therapeutic targets for future researches.

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A novel variant in the COL6A1 gene causing Ullrich congenital muscular dystrophy in a consanguineous family: a case report

BMC Neurology ◽

10.1186/s12883-021-02134-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Nirmala Dushyanthi Sirisena ◽

U. M. Jayami Eshana Samaranayake ◽

Osorio Lopes Abath Neto ◽

A. Reghan Foley ◽

B. A. P. Sajeewani Pathirana ◽

...

Keyword(s):

Muscular Dystrophy ◽

Motor Unit ◽

Muscle Weakness ◽

Congenital Muscular Dystrophy ◽

Clinical Severity ◽

Proximal Muscle Weakness ◽

Proximal Muscle ◽

Pathogenic Variants ◽

Ullrich Congenital Muscular Dystrophy ◽

Novel Variant

Abstract Background Collagen VI-related dystrophies are a subtype of congenital muscular dystrophy caused by pathogenic variants in COL6A1, COL6A2 or COL6A3 genes affecting skeletal muscles and connective tissue. The clinical phenotype ranges from the milder Bethlem myopathy to the severe Ullrich congenital muscular dystrophy (UCMD). Herein, we report the first consanguineous Sri Lankan family with two children affected with UCMD due to a novel variant in the COL6A1 gene. Case presentation Two sisters, aged 10-years and 7-years, presented with progressive, bilateral proximal muscle weakness. Both probands had delayed motor milestones and demonstrated difficulty in standing from a squatting position, climbing stairs and raising arms above the shoulders. Cognitive, language and social development were age appropriate. Examination showed proximal muscle weakness of the upper and lower extremities and hyperlaxity of the wrist and fingers in both with some variability in clinical severity noted between the two siblings. Serum creatine kinase levels were elevated, and electromyography showed low polyphasic motor unit potentials in the 10-year-old and myopathic features with short duration motor unit potentials with no polyphasia in the 7-year-old. Whole exome sequencing (WES) was performed and a novel, homozygous missense, likely pathogenic variant in exon 25 of COL6A1 gene [NM_001848: c.1667G > T;NP_001839.2:p.Gly556Val] was identified in both probands. This variant was validated by Sanger sequencing in proband 1 as well as proband 2, and the parents and an unaffected sibling were found to be heterozygote carriers for the same variant. Conclusions The findings in this family add to the expanding number of COL6A1 variants identified and provides a better understanding of the genotype-phenotype correlations associated with UCMD.

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Pathogenic variants in COL6A3 cause Ullrich-like congenital muscular dystrophy in young Labrador Retriever dogs

Neuromuscular Disorders ◽

10.1016/j.nmd.2020.03.005 ◽

2020 ◽

Vol 30 (5) ◽

pp. 360-367

Author(s):

Véronique Bolduc ◽

Katie M. Minor ◽

Ying Hu ◽

Rupleen Kaur ◽

Steven G. Friedenberg ◽

...

Keyword(s):

Muscular Dystrophy ◽

Congenital Muscular Dystrophy ◽

Labrador Retriever ◽

Pathogenic Variants

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Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent

10.1101/2020.09.15.20193425 ◽

2020 ◽

Cited By ~ 1

Author(s):

Samya Chakravorty ◽

Babi Ramesh Reddy Nallamilli ◽

Satish Khadilkar ◽

Madhubala Singla ◽

Ashish Bhutada ◽

...

Keyword(s):

Cohort Study ◽

Muscular Dystrophy ◽

Indian Subcontinent ◽

Congenital Muscular Dystrophy ◽

Gene Variant ◽

Autosomal Recessive Disorders ◽

Gne Myopathy ◽

Pathogenic Variants ◽

Myoadenylate Deaminase ◽

Recessive Disorders

Objective Inherited myopathies comprise more than 200 different individually rare disease-subtypes but when combined together have a high prevalence of 1 in 6000 individuals across the world. Our goal was to determine for the first time the clinical- and gene-variant spectrum of genetic myopathies in a substantial cohort study of the Indian subcontinent. Methods In this cohort-study, we performed the first large clinical exome sequencing (ES) study with phenotype correlation on 207 clinically well-characterized inherited myopathy-suspected patients from the Indian subcontinent with diverse ethnicities. Results Clinical-correlation driven definitive molecular diagnosis was established in 49% (101 cases; 95% CI, 42%-56%) of patients with the major contributing pathogenicity in either of three genes, GNE (28%; GNE-myopathy), DYSF (25%; Dysferlinopathy) and CAPN3 (19%; Calpainopathy). We identified 65 variant alleles comprising 37 unique variants in these three major genes. 78% of the DYSF patients were homozygous for the detected pathogenic variant suggesting the need for carrier-testing for autosomal-recessive disorders like Dysferlinopathy that are common in India. We describe the observed clinical spectrum of myopathies including uncommon and rare subtypes in India: Sarcoglycanopathies (SGCA/B/D/G), Collagenopathy (COL6A1/2/3), Anoctaminopathy (ANO5), telethoninopathy (TCAP), Pompe-disease (GAA), Myoadenylate-deaminase-deficiency-myopathy (AMPD1), myotilinopathy (MYOT), laminopathy (LMNA), HSP40-proteinopathy (DNAJB6), Emery-Dreifuss-muscular-dystrophy (EMD), Filaminopathy (FLNC), TRIM32-proteinopathy (TRIM32), POMT1-proteinopathy (POMT1), and Merosin-deficiency-congenital-muscular-dystrophy-type-1 (LAMA2). 13 Patients harbored pathogenic variants in >1 gene and had unusual clinical features suggesting a possible role of synergistic-heterozygosity / digenic-contribution to disease presentation and progression. Conclusions Application of clinically-correlated ES to myopathy diagnosis has improved our understanding of the clinical and genetic spectrum of different subtypes and their overlaps in Indian patients. This, in turn, will enhance the global gene-variant-disease databases by including data from developing countries/continents for more efficient clinically-driven molecular diagnostics.

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