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We describe an unusual movement disorder syndrome reminiscent of but distinct from Uner Tan syndrome.

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BackgroundDystonia involves repetitive movements and muscle contractions leading to abnormal postures. We investigated patients in two families, DYAF11 and M, exhibiting dystonic or involuntary movement disorders.MethodsClinical investigations were performed for all patients. Genetic analyses included genome-wide linkage analysis and exome sequencing followed by Sanger sequencing validation. MRM2-specific transcripts were analysed from participants’ blood samples in Family DYAF11 after cloning of gene-specific cDNA.ResultsFour affected siblings in Family DYAF11 had progressive dystonic features. Two patients in Family M exhibited a neurodevelopmental disorder accompanied by involuntary movements. In Family DYAF11, linkage was detected to the telomere at chromosome 7p22.3, spanning <2 Mb. Exome sequencing identified a donor splice-site variant, c.8+1G>T in MRM2, which segregated with the phenotype, corresponding to the linkage data since all affected individuals were homozygous while the obligate unaffected carriers were heterozygous for the variant. In the MRM2 c.8+1G>T allele, an aberrant alternative acceptor splice-site located within exon 2 was used in a subset of the transcripts, creating a frameshift in the open reading frame. Exome sequencing in Family M revealed a rare missense variant c.242C>T, p.(Ala81Val), which affected a conserved amino acid.ConclusionsOur results expand the clinical and allelic spectrum of MRM2 variants. Previously, these descriptions were based on observations in a single patient, diagnosed with mitochondrial DNA depletion syndrome 17, in whom movement disorder was accompanied by recurrent strokes and epilepsy. We also demonstrate a subset of correctly spliced tt-ag MRM2 transcripts, raising the possibility to develop treatment by understanding the disease mechanism.

Hemophilia A is the most common hereditary severe disorder of blood clotting. In families affected with hemophilia, genetic analysis provides opportunities to prevent recurrence of the disease. This study establishes a diagnostic strategy for carrier-ship determination in Pakistani population using an extragenic polymorphic marker for the first time. The analysis of St14 VNTR (DXS52) was carried out by polymerase chain reaction (PCR), in order to determine its informativeness in terms of heterozygosity in Pakistani population. This may be a milestone for further analysis of other polymorphic markers for carrier detection and prenatal diagnosis of hemophilia. Seventy eight blood samples (Hemophiliac = 23, Normal = 55) from 15 families were analyzed for determining informativeness of St14 VNTR in carrier detection of hemophilia A. A total of nine alleles (2400, 2100, 1750, 1690, 1630, 1570, 1390, 1300, 1220 bp) was detected in the pool of subjects. 19 out of 40 females were found to be carriers with respect to the St14 VNTR polymorphic marker. The marker was informative in 73.33% of families. The expected heterozygosity rate of the St14 VNTR was 0.86 while the observed heterozygosity was 0.7. This shows that St14 VNTR is 70% informative in our population, allowing it to be a useful marker in carrier detection, as informativeness is the direct reflection of heterozygosity of a polymorphic marker.