Mosaicism for GJB1 mutation causes milder Charcot-Marie-Tooth X1 phenotype in a heterozygous man than in a manifesting heterozygous woman

Abstract

Charcot-Marie-Tooth (CMT) disease is a heterogeneous disorder of the peripheral nervous system that collectively affects approximately 1 in 2,500 individuals, thus making it the most common inherited neurologic disorder. X-linked inheritance may account for 10-20 % of CMT neuropathy. We report a Czech family with a 30-year-old woman affected by CMT since the age of 10 years, originally as an isolated case. Nerve conduction study (NCS) showed demyelinating neuropathy, and DNA testing revealed a novel heterozygous gap junction beta-1 protein (GJB1) mutation c.784_786delTA. The same mutation, but surprisingly in heterozygous state, was subsequently found in her subjectively healthy father and later also in one of her sisters but not in her two other sisters. NCS showed intermediate type of motor and sensory neuropathy in these two females manifesting heterozygotes and normal results in the other healthy sisters and one brother, all without the c.784_786delTA mutation. The father has a phenotype milder than his daughter and has only subclinical signs of CMT. The index female patient had normal karyotype 46, XX, and normal FISH for centromeric X chromosome. We concluded that the proband's father is a heterozygote due to the somatic mosaicism for the GJB1 mutation in his leukocytes (detected by DNA sequencing) and also in his germ cells as confirmed by the unexpectedly different genotypes in his four daughters. Quantitative analysis revealed a mutated signal in 25:75 allele proportion of mutated to healthy allele in the mosaic father. This study has important consequences for genetic counseling and prognosis in CMTX1 families.

ATP1A1mutations cause intermediate Charcot‐Marie‐Tooth disease

“…Mosaicism has been previously reported in other forms of CMT. The clinical manifestation of mosaic status was always present later onset and milder form of the disease, including asymptomatic with normal neurophysiology (Borgulová et al, ; McLaughlin et al, ; Schon et al, ; Spinner & Conlin, ). Hence, the proband's mother was most likely to be explained by the somatic mosaicism.…”

Mosaicism for a pathogenic MFN2 mutation causes minimal clinical features of CMT2A in the parent of a severely affected child

“…Mosaicism has been previously reported in other forms of CMT, with a very variable clinical phenotype including asymptomatic with normal neurophysiology studies [12], subclinical disease [13], mild clinical disease [14–16] and typical presentations of CMT1A with somatic mosaicism found on genetic testing [17–19]. The mutations, level of mosaicism, clinical features and neurophysiology findings from the literature are summarised Table 1.…”

“…Individuals with mild or subclinical CMT due to somatic mosaicism who have been ascertained through an affected child (or grandchild) have been described for CMT1A [16] , CMTX1 [13, 14], and CMT1E [15]. …”

A Novel TAZ Gene Mutation and Mosaicism in a Polish Family with Barth Syndrome

“…Mosaicism can be tissue-specific or tissue-limited (Biesecker & Spinner, 2013 ) which is why we performed genetic testing of two different somatic tissues (mesoderm-derived lymphocytes and ectoderm-derived buccal epithelial cells). At the moment, there is only one scientific report on the occurrence of mosaicism in Barth syndrome (Chang et al, 2010 ) but many on the presence of different mosaicism types in other genetic diseases coupled with the X or autosomal chromosomes have been reported (Bakker et al, 1987 ; Puck et al, 1995 ; Forissier et al, 2000 ; Barbosa et al, 2008 ; Chiang et al, 2009 ; Alsina et al, 2013 ; Borgulová et al, 2013 ; Dufendach et al, 2013 ). In this family, it was found that the mutation p.Val28Glu is present in ectodermal as well as in mesodermal cells in the proband's grandmother and male cousin, whereas in samples taken from the proband's mother and aunts the mutation is present only in mesodermal peripheral blood cells or at a low level of mosaicism in ectodermal buccal epithelial cells.…”