PMC6491636_01
Pedigree of the family compiled with X-linked dominant inheritance. Square represents male and circle represents female. Filled symbol indicates affected. Dot symbol indicates deduced affected individual with medical history. A slash through a symbol indicates deceased individual. Arrow indicates the proband. The symbol "+" indicates a carrier of the variant. The symbol "-" indicates wild genotype. No symbol means the individual's genetic test is not available. The pedigree has been edited to maintain the confidentiality of family members.
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F1
The proband (IV-1 in Figure 1), a 28-year-old man, was admitted into our department for recurrent dysphonia and asymmetric weakness of four limbs with the right side more severely affected. Pedigree analysis indicates an X-linked dominant inheritance (Figure 1). It is located in the nerve-specific promoter P2 region of GJB1, neighboring c.-171G>C (designated as c.-146-25 G>C in the earlier edition of HGMD, Figure 4G), which has been shown reducing the expression of Cx32. c.-170T>G cosegragated with the disease in this pedigree (Figure 1, Figures 4B-F) and was not present in 100 control DNA samples.
The brain MRI images of the proband. In the "stroke-like" episode, brain MRI showed slightly hypointensity in T1-weighted imaging (A) and slightly hyperintensity in T2-weighted imaging (B) in the bilateral deep white matter and the splenium of the corpus callosum. But there was obviously bilaterally symmetric hyperintensity in T2 FLAIR images and reduced diffusion in the same region (C,D). MRI after 8 days showed improvement of the abnormal diffusion signal in white matter (E). After 5 months, the images of T1-weighted (F), T2-weighted (G), T2 FLAIR (H), and DWI (I) of his brain were almost normal.
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F2
FLAIR hyperintensity in the deep white matter and the splenium of the corpus callosum (Figure 2C) and reduced diffusion (Figure 2D). The diffusion reduction disappeared mostly 8 days later (Figure 2E). Five months after the episode, the MRI of his brain were almost normal (Figures 2F-I).
The pictures of III-8's limbs. He had atrophy of distal muscles below the knee and in the hands with cavus deformity.
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F3
III-8 presented typically with all the features above (Figure 3).
Sequencing results of GJB1 and its schematic representation of the proximal Cx32 promoter region. (A) The proband had a hemizygous c.-170T>G variant. (B) III-1, the mother of the proband, had a heterozygous c.-170T>G. (C,D) III-1, the father of the proband and IV-2, the brother of the proband, were both wild genotype. (E) II-2, a 93-year old woman and the grandma of the proband without any clinical manifestation, carried a heterozygous c.-170T>G. (F) III-8, an affected male with typical neuromuscular manifestations had hemizygous c.-170T>G. (G) Schematic representation of the proximal Cx32 promoter region which indicates the positions of SOX10 (S1 and S2) and EGR2 (E1, E2, and E3) binding sites. GJB1 has 2 tissue-specific promoters (P1 and P2) which are alternatively spliced. In neural tissue, GJB1 transcription is driven via the nerve-specific promoter 2 (P2) upstream of non-coding exon 1b. Up to now, four mutations in the P2 region have been reported (indicated with asterisk). The c.-170T>G variant identified in this pedigree (red) neighbors c.-171G>C which has been proved impairing SOX10-mediated transcription of GJB1. This figure was modified from Neurology 2017;88:1445-1453. with permission.
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F4
A novel hemizygous variant c.-170T>G was found (Figure 4A). It is located in the nerve-specific promoter P2 region of GJB1, neighboring c.-171G>C (designated as c.-146-25 G>C in the earlier edition of HGMD, Figure 4G), which has been shown reducing the expression of Cx32. c.-170T>G cosegragated with the disease in this pedigree (Figure 1, Figures 4B-F) and was not present in 100 control DNA samples.