Congenital myopathy

Gene: MLIP

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 26 Sep 2024, 10:39 a.m. | Last Modified: 26 Sep 2024, 10:39 a.m.

Panel Version: 4.42

Comment on classification of this gene: The rating for this gene should be GREEN, as this gene has been implicated in congenital myopathy, as identified from biallelic variants from ten unrelated cases from multiple ethnicities and supported by results from functional studies from human tissue samples and mouse models.

Seven patients from six families carrying six different biallelic (either homozygous or compound heterozygous) variants in MLIP gene were presented with a consistent phenotype including mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase (CK) levels. The age of onset of symptoms ranged from 8 months to 7 years (PMID:34581780).

Five individuals from two different pedigrees carrying two different novel homozygous nonsense variants were reported with myopathy characterized by hyperCKemia and with absence of rhabdomyolysis. The age of onset of symptoms for the single patient from family 1 is 2.5 years. All four individuals (age ranges from 24 to 37) from family 2 (Amish ancestry) were reported either with Sinus arrhythmia or Sinus bradycardia. It was also found that there is founder effect for this allele in the Amish population in the resident county of these individuals (PMID:34935254). Another patient harbouring a nonsense homozygous variant was reported with an adult-onset myopathy since the age of 50 after presenting poor sports performance since childhood and without any cardiac involvement (PMID:35672413). Similarly, an 80 year old patient with homozygous variant was also reported with progressive muscle disease and myocardiopathy was absent despite his age (PMID:35915960).

The expression of MLIP was identified to be reduced in patients with dilated cardiomyopathy, as studied from LV samples from patients with terminal-stage heart failure. In addition, deletion of MLIP gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models and overexpression prevented pathologic remodelling and preserved cardiac function (PMID:26436652). MLIP has also been identified as a regulator of myoblast differentiation (PMID:33802236) and myonuclear positioning (PMID:32719146).

MLIP has now been associated with myopathy in OMIM (#620138).

Created: 11 Dec 2022, 9:17 p.m. | Last Modified: 11 Dec 2022, 9:17 p.m.

Panel Version: 3.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138

Publications

• 26436652
• 32719146
• 33802236
• 34581780
• 34935254
• 35672413
• 35915960
• 35942668

Green List (high evidence)

PMID: 34581780: 7 individuals with 6 families with truncating (one splice that also resulted in a frameshift variant) biallelic variants (used NM_1281746).

In 3 patients patients’ skeletal muscle, these variants were shown to cause reduction overall RNA expression levels of the predominant MLIP isoform.

Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels.
Sources: Literature

Created: 4 Dec 2021, 8:03 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
MLIP-related myopathy with rhabdomyolysis

Publications

• 34581780