RT Journal Article
SR Electronic
T1 Manifesting carriers of X-linked myotubular myopathy
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e513
DO 10.1212/NXG.0000000000000513
VO 6
IS 5
A1 Lucas Santos Souza
A1 Camila Freitas Almeida
A1 Guilherme Lopes Yamamoto
A1 Rita de Cássia Mingroni Pavanello
A1 Juliana Gurgel-Giannetti
A1 Silvia Souza da Costa
A1 Isabela Pessa Anequini
A1 Silvana Amanda do Carmo
A1 Jaqueline Yu Ting Wang
A1 Marília de Oliveira Scliar
A1 Erick C. Castelli
A1 Paulo Alberto Otto
A1 Edmar Zanoteli
A1 Mariz Vainzof
YR 2020
UL http://ng.neurology.org/content/6/5/e513.abstract
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