To analyze the modulation of the phenotype in manifesting carriers of recessive X-linked myotubular myopathy (XLMTM), searching for possible genetic modifiers.

Twelve 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.

Mutations 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.

Affected 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.

分析隐性 X 连锁肌管肌病 (XLMTM) 携带者表型的调节，寻找可能的遗传修饰因子。

对 12 个患有 XLMTM 的巴西家庭进行了分子和临床评估。在 2 个家庭中，确定了 6 个中有 4 个和 5 个有表现的女性携带者中的 2 个。对这些雌性进行了 X 染色体失活研究。此外，还进行了全外显子组测序，寻找可能的修饰变体。我们还确定了导致该疾病的突变携带者的外显率。

MTM1基因的突变在来自 12 个家庭的所有指示患者中都被鉴定出，其中 4 个是新的。在杂合子中，X 染色体失活在 4 名信息显示携带者中的 3 名中是随机的。疾病外显率估计为 30%，与不完全外显率相符。外显子组比较分析确定了 19 号染色体上 4.2 Mb 片段内的变异，其中包含存在于所有非表现携带者中且不存在于所有表现载体中的杀伤细胞免疫球蛋白样受体基因簇。我们假设这些杀伤细胞免疫球蛋白样受体变体可能调节表型，在非表现载体中充当保护因素。

受影响的 XLMTM 女性携带者被描述为隐性 X 连锁疾病的高频率，这引发了关于遗传模式或修饰因子作用于疾病表型的作用的问题。我们证明了这些女性的临床表现可能存在遗传机制和变异，这可能成为未来治疗的目标。