Manifesting carriers of X-linked myotubular myopathy

Abstract

ObjectiveTo analyze the modulation of the phenotype in manifesting carriers of recessive X-linked myotubular myopathy (XLMTM), searching for possible genetic modifiers.MethodsTwelve Brazilian families with XLMTM were molecularly and clinically evaluated. In 2 families, 4 of 6 and 2 of 5 manifesting female carriers were identified. These females were studied for X chromosome inactivation. In addition, whole-exome sequencing was performed, looking for possible modifier variants. We also determined the penetrance rate among carriers of the mutations responsible for the condition.ResultsMutations in the MTM1 gene were identified in all index patients from the 12 families, being 4 of them novel. In the heterozygotes, X chromosome inactivation was random in 3 of 4 informative manifesting carriers. The disease penetrance rate was estimated to be 30%, compatible with incomplete penetrance. Exome comparative analyses identified variants within a segment of 4.2 Mb on chromosome 19, containing the killer cell immunoglobulin-like receptor cluster of genes that were present in all nonmanifesting carriers and absent in all manifesting carriers. We hypothesized that these killer cell immunoglobulin-like receptor variants may modulate the phenotype, acting as a protective factor in the nonmanifesting carriers.ConclusionsAffected XLMTM female carriers have been described with a surprisingly high frequency for a recessive X-linked disease, raising the question about the pattern of inheritance or the role of modifier factors acting on the disease phenotype. We demonstrated the possible existence of genetic mechanisms and variants accountable for the clinical manifestation in these women, which can become future targets for therapies.

Myogenesis defects in a patient-derived iPSC model of hereditary GNE myopathy

“…For example, inherited myopathies, including GNEM, can manifest with intrafamilial variability in regard to clinical phenotype, age of onset, or disease progression 29 – 31 . In addition, there is evidence of genetic modifiers accompanying the primary mutation or modulating the phenotype 32 , 33 . Therefore, a model system able to capture gene variability while also recapitulating the key pathological characteristics becomes crucial for elucidating yet-to-be discovered contributors to disease etiology.…”

Spectrum of Clinical Features in X-Linked Myotubular Myopathy Carriers

“…However, previous literature suggests that these mechanisms on their own cannot explain the phenotype in all carriers and that additional disease-modifying factors very likely exist. 14,15,18 For example, a recent article by Souza et al 17 has suggested killer cell immunoglobulin-like receptor mutations as genetic modifiers in manifesting XL-MTM carriers, with a potentially protective role suggested by their presence in nonmanifesting carriers and their absence in manifesting carriers.…”

“…[9][10][11][12][13][14][15][16] Manifestations in these carriers may be due to skewed X-chromosomal inactivation or other X-chromosomal alterations, but additional modifiers have also been considered. 10,12,15,17 There is probably a reporting bias in the literature toward the most severely affected carriers. 9,12,14 Symptoms in XL-MTM carriers have recently been systematically investigated in 2 large cohorts.…”

Myogenesis defects in a patient-derived iPSC model of hereditary GNE myopathy

“…For example, inherited myopathies, including GNE myopathy, can manifest with intrafamilial variability in regard to clinical phenotype, age of onset, or disease progression (Dotti et al, 2018;Stober et al, 2010;Diniz et al, 2016). In addition, there is evidence of genetic modifiers, accompanying the primary mutation, modulating the phenotype (Bello et al, 2016;Souza et al, 2020). Therefore, a model system able to capture gene variability while also recapitulating the key pathological characteristics becomes crucial for elucidating yet-to-be discovered contributors to disease etiology.…”