LMNA-related muscular dystrophy: Identification of variants in alternative genes and personalized clinical translation

Abstract

Background: Laminopathies are caused by rare alterations in LMNA, leading to a wide clinical spectrum. Though muscular dystrophy begins at early ages, disease progression is different in each patient. We investigated variability in laminopathy phenotypes by performing a targeted genetic analysis of patients diagnosed with LMNA-related muscular dystrophy to identify rare variants in alternative genes, thereby explaining phenotypic differences.Methods: We analyzed 105 genes associated with muscular diseases by targeted sequencing in 26 pediatric patients of different countries, diagnosed with any LMNA-related muscular dystrophy. Family members were also clinically assessed and genetically analyzed.Results: All patients carried a pathogenic rare variant in LMNA. Clinical diagnoses included Emery-Dreifuss muscular dystrophy (EDMD, 13 patients), LMNA-related congenital muscular dystrophy (L-CMD, 11 patients), and limb-girdle muscular dystrophy 1B (LGMD1B, 2 patients). In 9 patients, 10 additional rare genetic variants were identified in 8 genes other than LMNA. Genotype-phenotype correlation showed additional deleterious rare variants in five of the nine patients (3 L-CMD and 2 EDMD) with severe phenotypes.Conclusion: Analysis f known genes related to muscular diseases in close correlation with personalized clinical assessments may help identify additional rare variants of LMNA potentially associated with early onset or most severe disease progression.

Congenital LMNA-Related Muscular Dystrophy in Paediatrics: Cardiac Management in Monozygotic Twins

“…The updated data showed that only two of these rare variants maintained an ambiguous role, and the third rare variant could be classified as benign. Therefore, we suspect the pathogenic variant in the LMNA gene to be the cause of the disease, but our hypothesis highlights that the combination of rare variants in different genes may lead to a more severe phenotype, or at least to the early onset of symptoms reported in L-CMD, as previously reported by our group [ 6 ]. This is in accordance with recent studies suggested that digenic models of inheritance may explain the incomplete penetrance/variable expressivity observed in neuromuscular entities [ 12 ].…”

“…Limited numbers of diagnosed cases of L-CMD have been reported so far. Our group published a series of paediatric cases including monozygotic twins [ 4 , 6 ]. Here, we present a complete clinical assessment ( Table 1 ; Figure 1 , Figure 2 and Figure 3 ) and genetic analysis ( Table 2 ) in twins and their parents and siblings, including a close follow-up ( Figure 4 ).…”

“…Clinical evaluation of all family members included a complete physical examination by a paediatric neurologist and paediatric cardiologist in children, as well as by a neurologist and cardiologist in the parents, as previously published [ 4 , 6 ]. Baseline cardiac work-up consisted of a transthoracic Doppler echocardiography, a 12-lead electrocardiogram (ECG), electrophysiological study (EPS), and the implantation of a long-term cardiac implantable loop recorder with a home monitoring system.…”

“…Our group proposed the first cardiac algorithm for the early identification and prevention of malignant arrhythmias in paediatric cases [ 4 ]. In addition, we reported a comprehensive genetic analysis in order to unravel novel rare variants in other genes related to neuromuscular diseases explaining potential differences in the time of onset and/or time-evolution in L-CMD cases [ 6 ]. The revaluation of rare variants, especially if previously classified with an ambiguous role, should be performed periodically until a definite role in muscular dystrophies has been clarified [ 7 ].…”

Creatine and l-carnitine attenuate muscular laminopathy in the LMNA mutation transgenic zebrafish

“…Specifically, a CMD patient exhibited LMNA (c.104T>C), resulting in an amino acid change from leucine to proline [p. Leu35Pro or LMNA (L35P)] 11 . An EDMD family, consisting of a grandfather, mother and daughter, displayed EDMD with LMNA (c.1616C>T), leading to an alanine-to-valine alteration [p.Ala539Val or LMNA (A539V)] 12 . Another EDMD family, comprising a mother and two daughters, showcased LMNA (c.1558T>G), causing tryptophan to become glycine [p.Trp520Gly or LMNA (W520G)] 13 .…”