PT  - JOURNAL ARTICLE
AU  - Lucas Santos Souza
AU  - Camila Freitas Almeida
AU  - Guilherme Lopes Yamamoto
AU  - Rita de Cássia Mingroni Pavanello
AU  - Juliana Gurgel-Giannetti
AU  - Silvia Souza da Costa
AU  - Isabela Pessa Anequini
AU  - Silvana Amanda do Carmo
AU  - Jaqueline Yu Ting Wang
AU  - Marília de Oliveira Scliar
AU  - Erick C. Castelli
AU  - Paulo Alberto Otto
AU  - Edmar Zanoteli
AU  - Mariz Vainzof
TI  - Manifesting carriers of X-linked myotubular myopathy
AID  - 10.1212/NXG.0000000000000513
DP  - 2020 Oct 01
TA  - Neurology Genetics
PG  - e513
VI  - 6
IP  - 5
4099  - http://ng.neurology.org/content/6/5/e513.short
4100  - http://ng.neurology.org/content/6/5/e513.full
SO  - Neurol Genet2020 Oct 01; 6
AB  - Objective To analyze the modulation of the phenotype in manifesting carriers of recessive X-linked myotubular myopathy (XLMTM), searching for possible genetic modifiers.Methods 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.Results 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.Conclusions 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.CMs=congenital myopathies; CNM=centronuclear myopathy; DMD=Duchenne muscular dystrophy; FVC=forced vital capacity; KIR=killer cell immunoglobulin-like receptor; MC=manifesting carrier; MMT=manual muscle testing; NMC=nonmanifesting carrier; XCI=X chromosome inactivation; XLMTM=X-linked myotubular myopathy