Novel phenotypic variant in the MYH7 spectrum due to a stop-loss mutation in the C-terminal region: a case report.

BACKGROUND: Defects of the slow myosin heavy chain isoform coding MYH7 gene primarily cause skeletal myopathies including Laing Distal Myopathy, Myosin Storage Myopathy and are also responsible for cardiomyopathies. Scapuloperoneal and limb-girdle muscle weakness, congenital fiber type disproportion, multi-minicore disease were also reported in connection of MYH7. Pathogeneses of the defects in the head and proximal rod region of the protein are well described. However, the C-terminal mutations of the MYH7 gene are less known. Moreover, only two articles describe the phenotypic impact of the elongated mature protein product caused by termination signal loss. CASE PRESENTATION: Here we present a male patient with an unusual phenotypic variant of early-onset and predominant involvement of neck muscles with muscle biopsy indicating myopathy and sarcoplasmic storage material. Cardiomyopathic involvements could not be observed. Sequencing of MYH7 gene revealed a stop-loss mutation on the 3-prime end of the rod region, which causes the elongation of the mature protein. CONCLUSIONS: The elongated protein likely disrupts the functions of the sarcomere by multiple functional abnormalities. This elongation could also affect the thick filament degradation leading to protein deposition and accumulation in the sarcomere, resulting in the severe myopathy of certain axial muscles. The phenotypic expression of the detected novel MYH7 genotype could strengthen and further expand our knowledge about mutations affecting the structure of MyHCI by termination signal loss in the MYH7 gene.

Correction to: Novel phenotypic variant in the MYH7 spectrum due to a stop-loss mutation in the C-terminal region: a case report.

Following publication of the original article [1], the authors requested a correction to the details of one of the co-authors.

Admixture of beneficial and unfavourable variants of GLCCI1 and FCER2 in Roma samples can implicate different clinical response to corticosteroids.

Variants of glucocorticoid induced transcript 1 (GLCCI1) result decreased response to inhaled corticosteroids, while intronic variant of low-affinity IgE receptor (FCER2) is associated with exacerbation rates in children with asthma. We examined the ethnic differences, allele and genotype frequencies of two linked single nucleotide polymorphisms (rs37972, rs37973) of GLCCI1 and rs28364072 intronic variant of FCER2 gene in average Roma and Hungarian population. A study population of 474 healthy Roma and 397 Hungarian subjects were characterized for GLCCI1 and FCER2 polymorphisms using real time polymerase chain reaction (PCR) assay and PCR-restriction fragment length polymorphism method. The rs37972 and rs37973 polymorphisms in GLCCI1 were found in 100% linkage disequilibrium both in Romas and in Hungarians. We found significant differences between the two groups regarding both minor allele frequencies (54.5 vs. 43.8%, p ≤ 0.01) and homozygous genotype (31.6 vs. 21.3%, p ≤ 0.01) of GLCCI1. For FCER2 rs28364072 the homozygous variant genotype was present in 2.8% in Romas, while in Hungarians it was 5.8% (p = 0.032). The opposite changes of these two polymorphisms strongly suggest that contrary current belief analyses of GLCCI1 variants are insufficient for personalised glucocorticoid therapies in different populations.

Lower carrier rate of GJB2 W24X ancestral Indian mutation in Roma samples from Hungary: implication for public health intervention.

The purpose of this work was to characterise the W24X mutation of the GJB2 gene in order to provide more representative and geographicaly relevant carrier rates of healthy Roma subisolates and the Hungarian population. 493 Roma and 498 Hungarian healthy subjects were genotyped for the GJB2 c.71G>A (rs104894396, W24X) mutation by PCR-RFLP assay and direct sequencing. This is the first report on GJB2 W24X mutation in geographically subisolated Roma population of Hungary compared to local Hungarians. Comparing the genotype and allele frequencies of GJB2 rs104894396 mutation, significant difference was found in GG (98.4 vs. 99.8 %), GA (1.62 vs. 0.20 %) genotypes and A (0.8 vs. 0.1 %) allele between the Roma and Hungarian populations, respectively (p < 0.02). None of the subjects of Roma and Hungarian samples carried the GJB2 W24X AA genotype. Considerable result of our study, that the proportion of GJB2 W24X GA heterozygotes and the A allele frequency was eight times higher in Roma than in Hungarians. Considering the results, the mutant allele frequency both in Roma (0.8 %) and in Hungarian (0.1 %) populations is lower than expected from previous results, likely reflecting local differentiated subisolates of these populations and a suspected lower risk for GJB2 mutation related deafness. However, the significant difference in GJB2 W24X carrier rates between the Roma and Hungarians may initiate individual diagnostic investigations and effective public health interventions.

[Attention deficit hyperactivity disorder analyzed with array comparative genome hybridization method. Case report]. / Figyelemhiányos hiperaktivitásban szenvedo beteg vizsgálata array komparatív genomhibridizációs módszerrel.

One of the most common psychiatric disorders during childhood is attention deficit hyperactivity disorder, which affects 5-6% of children worldwide. Symptoms include attention deficit, hyperactivity, forgetfulness and weak impulse control. The exact mechanism behind the development of the disease is unknown. However, current data suggest that a strong genetic background is responsible, which explains the frequent occurrence within a family. Literature data show that copy number variations are very common in patients with attention deficit hyperactivity disorder. The authors present a patient with attention deficit hyperactivity disorder who proved to have two approximately 400 kb heterozygous microduplications at 6p25.2 and 15q13.3 chromosomal regions detected by comparative genomic hybridization methods. Both duplications affect genes (6p25.2: SLC22A23; 15q13.3: CHRNA7) which may play a role in the development of attention deficit hyperactivity disorder. This case serves as an example of the wide spectrum of indication of the array comparative genome hybridization method.

Increased prevalence of functional minor allele variants of drug metabolizing CYP2B6 and CYP2D6 genes in Roma population samples.

BACKGROUND: Cytochrome P450 2B6 and 2D6 are important enzymes in human drug metabolism. These phase I enzymes are known to contribute the biotransformation of clinically important pharmaceuticals, including antidepressants, anticancer and anxiolytic drugs. The aim of this work was to determine the pharmacogenetic profile of CYP2B6 and CYP2D6 in Roma and Hungarian population samples. METHODS: A study population of 426 healthy Roma and 431 healthy Hungarian subjects were characterized for CYP2B6 c.516G>T, CYP2D6 c.100C>T and c.1846G>A polymorphisms using predesigned TaqMan Drug Metabolism Genotyping Real Time-PCR assays. RESULTS: We found significant differences in the presence of CYP2B6 c.516G>T (p<0.001), CYP2D6 c.100C>T (p=0.003) and c.1846G>A (p=0.022) between Hungarian and Roma population. The 516T allele frequency was 33.6% in the Roma group, 21.4% in Hungarians, whereas the minor CYP2D6 100T allele was present in 26.6% in Romas and 20.5% in Hungarians. The 1864A allele frequency was 22.5% in Roma and 18.1% in Hungarian samples. A significant increase was found in genotype frequencies for homozygous minor allele carrier Roma participants compared to Hungarians for CYP2B6 516TT and CYP2D6 100TT. The following CYP2D6 genotypes were identified in Roma samples: *1/*1 (55.4%), *1/*4 (2.1%), *1/*10 (3.1%), *4/*10 (38.7%), *10/*10 (0.7%). CONCLUSION: Our results demonstrate an increased minor allele frequency for CYP2B6 and CYP2D6 polymorphisms in Roma samples that implies clinical significance in this ethnic group.