Manifesting carriers of X-linked myotubular myopathy Genetic modifiers modulating the phenotype

Author(s):Show less -

Souza, Lucas Santos ^[1] ; Almeida, Camila Freitas ^[1] ; Yamamoto, Guilherme Lopes ^[1] ; Mingroni Pavanello, Rita de Cassia ^[1] ; Gurgel-Giannetti, Juliana ^[2] ; da Costa, Silvia Souza ^[1] ; Anequini, Isabela Pessa ^[1] ; do Carmo, Silvana Amanda ^[1] ; Wang, Jaqueline Yu Ting ^[1] ; Scliar, Marilia de Oliveira ^[1] ; Castelli, Erick C. ^[3] ; Otto, Paulo Alberto ^[1] ; Zanoteli, Edmar ^[4] ; Vainzof, Mariz ^[1]

Affiliation

^[1] Univ Sao Paulo, Human Genome & Stem Cell Res Ctr, Sao Paulo - Brazil

^[2] Univ Fed Minas Gerais, Med Sch, Dept Pediat, Belo Horizonte, MG - Brazil

^[3] Sao Paulo State Univ UNESP, Sch Med, Pathol Dept, Botucatu, SP - Brazil

^[4] Univ Sao Paulo, Dept Neurol, Med Sch FMUSP, Sao Paulo - Brazil

• Document type: Journal article
• Source: NEUROLOGY-GENETICS; v. 6, n. 5 OCT 2020.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC