BACKGROUND: The Roma are a European ethnic minority threatened by several recessive diseases. Variants in MANBA cause a rare lysosomal storage disorder named beta-mannosidosis whose clinical manifestation includes deafness and mental retardation. Since 1986, only 23 patients with beta-mannosidosis and biallelic MANBA variants have been described worldwide. RESULTS: We now report on further 10 beta-mannosidosis patients of Roma origin from eight families in the Czech and Slovak Republics with hearing loss, mental retardation and homozygous pathogenic variants in MANBA. MANBA variant c.2158-2A>G screening among 345 anonymized normal hearing controls from Roma populations revealed a carrier/heterozygote frequency of 3.77%. This is about 925 times higher than the frequency of this variant in the gnomAD public database and classifies the c.2158-2A>G variant as a prevalent, ethnic-specific variant causing hearing loss and mental retardation in a homozygous state. The frequency of heterozygotes/carriers is similar to another pathogenic variant c.71G>A (p.W24*) in GJB2, regarded as the most frequent variant causing deafness in Roma populations. CONLCUSION: Beta-mannosidosis, due to a homozygous c.2158-2A>G MANBA variant, is an important and previously unknown cause of hearing loss and mental retardation among Central European Roma.

• Keywords
• Beta-mannosidosis, Ethnic-specific variant, Hearing loss, Mental retardation, Roma,
• MeSH
• beta-Mannosidosis * MeSH
• Ethnicity MeSH
• Deafness * genetics   MeSH
• Humans MeSH
• Minority Groups MeSH
• Hearing Loss * genetics   MeSH
• Roma * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH
• Slovakia epidemiology   MeSH

BACKGROUND: In the present study we aimed: 1) To establish the prevalence and clinical impact of DFNB49 mutations in deaf Roma from 2 Central European countries (Slovakia and Hungary), and 2) to analyze a possible common origin of the c.1331+2T>C mutation among Roma and Pakistani mutation carriers identified in the present and previous studies. METHODS: We sequenced 6 exons of the MARVELD2 gene in a group of 143 unrelated hearing impaired Slovak Roma patients. Simultaneously, we used RFLP to detect the c.1331+2T>C mutation in 85 Hungarian deaf Roma patients, control groups of 702 normal hearing Romanies from both countries and 375 hearing impaired Slovak Caucasians. We analyzed the haplotype using 21 SNPs spanning a 5.34Mb around the mutation c.1331+2T>C. RESULTS: One pathogenic mutation (c.1331+2T>C) was identified in 12 homozygous hearing impaired Roma patients. Allele frequency of this mutation was higher in Hungarian (10%) than in Slovak (3.85%) Roma patients. The identified common haplotype in Roma patients was defined by 18 SNP markers (3.89 Mb). Fourteen common SNPs were also shared among Pakistani and Roma homozygotes. Biallelic mutation carriers suffered from prelingual bilateral moderate to profound sensorineural hearing loss. CONCLUSIONS: We demonstrate different frequencies of the c.1331+2T>C mutation in hearing impaired Romanies from 3 Central European countries. In addition, our results provide support for the hypothesis of a possible common ancestor of the Slovak, Hungarian and Czech Roma as well as Pakistani deaf patients. Testing for the c.1331+2T>C mutation may be recommended in GJB2 negative Roma cases with early-onset sensorineural hearing loss.

• MeSH
• Alleles MeSH
• Founder Effect MeSH
• Exons genetics   MeSH
• Gene Frequency MeSH
• Genotype MeSH
• Haplotypes genetics   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Infant MeSH
• Connexin 26 MeSH
• Connexins MeSH
• Humans MeSH
• MARVEL Domain Containing 2 Protein genetics   MeSH
• Mutation * MeSH
• Hearing Loss congenital   ethnology   genetics   MeSH
• Prevalence MeSH
• Roma genetics   MeSH
• Sequence Homology, Nucleic Acid MeSH
• Age of Onset MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Comparative Study MeSH
• Geographicals
• Czech Republic ethnology   MeSH
• Hungary ethnology   MeSH
• Pakistan ethnology   MeSH
• Slovakia ethnology   MeSH
• Names of Substances
• GJB2 protein, human MeSH Browser
• Connexin 26 MeSH
• Connexins MeSH
• MARVELD2 protein, human MeSH Browser
• MARVEL Domain Containing 2 Protein MeSH