Xp11.2 Duplication in Females: Unique Features of a Rare Copy Number Variation.

Among the diseases with X-linked inheritance and intellectual disability, duplication of the Xp11.23p11.22 region is indeed a rare phenomenon, with less than 90 cases known in the literature. Most of them have been recognized with the routine application of array techniques, as these copy number variations (CNVs) are highly variable in size, occurring in recurrent and non-recurrent forms. Its pathogenic role is not debated anymore, but the information available about the pathomechanism, especially in affected females, is still very limited. It has been observed that the phenotype in females varies from normal to severe, which does not correlate with the size of the duplication or the genes involved, and which makes it very difficult to give an individual prognosis. Among the patients studied by the authors because of intellectual disability, epilepsy, and minor anomalies, overlapping duplications affecting the Xp11.23p11.22 region were detected in three females. Based on our detailed phenotype analysis, we concluded that Xp11.23p11.22 duplication is a neurodevelopmental disorder.

Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type.

LGMD1D is an autosomal dominant limb girdle muscular dystrophy caused by variants in the DNAJB6 gene. This is typically an adult-onset disorder characterized by moderately progressive proximal muscle weakness without respiratory or bulbar involvement; however phenotypic variability is often observed with some individuals having earlier onset and more severe symptoms. Here, we present a family with a novel NM_005494.2:c.271T > G p.(Phe91Val) variant in DNAJB6 with a late-onset, mild and slowly progressive form of the disease, including one individual, who in her 7th decade of life has subclinical LGMD1D with only mild features on muscle biopsy and MRI. Unlike previously reported cases where missense variants affecting the Phe91 amino acid residue are associated with a more severe form of the disease, this family represents the mild end of the LGMD1D clinical spectrum. Therefore, this family adds further complexity to the genotype-phenotype correlation in DNAJB6-associated muscular dystrophies.

Mutation spectrum of the SCN1A gene in a Hungarian population with epilepsy.

PURPOSE: The vast majority of mutations responsible for epilepsy syndromes such as genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS) occur in the gene encoding the type 1 alpha subunit of neuronal voltage-gated sodium channel (SCN1A). METHODS: 63 individuals presenting with either DS or GEFS + syndrome phenotype were screened for SCN1A gene mutation using Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). RESULTS: Our research study identified 15 novel pathogen mutations in the SCN1A gene of which 12 appeared to be missense mutations with addition of two frameshift-deletions and one in-frame deletion. The distribution of clinical phenotypes in patients carrying SCN1A mutations was as follows: twelve patients had classical DS, three patients had GEFS + syndrome and two relatives of DS patients were suffering from febrile seizures. CONCLUSIONS: Our study highlights the phenotypic and genotypic heterogeneities of DS and GEFS + with the important aim of gaining a deeper understanding of SCN1A-related disorders. This study also represents the first genetic analysis of the SCN1A gene in a Hungarian cohort with the DS and GEFS + syndrome phenotype.

A novel pathogenic variant in TNPO3 in a Hungarian family with limb-girdle muscular dystrophy 1F.

Limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous muscular diseases that predominantly affect the proximal muscles. Pathogenic variants in TNPO3 have been associated with a rare, autosomal dominant limb-girdle muscular dystrophy 1F (LGMD1F) in a large Italian-Spanish family and an isolated LGMD1F case. Here we present two individuals from a Hungarian family with an early-onset, slowly progressive muscular dystrophy. Both the female proband and her affected son had delayed early motor milestones including first walking at 14 months and 18 months, respectively. Both present with progressive weakness of facial, bulbar, axial, and distal muscles especially of the lower extremities. Electromyography indicated myogenic damage and muscle biopsy from the proband showed myopathic alterations with sarcoplasmic masses and signs of mitochondrial dysfunction. Exome sequencing of the female proband identified a novel c.2767delC p.(Arg923AspfsTer17) variant in TNPO3. Sanger sequencing confirmed the presence of the TNPO3 variant in the affected son; the unaffected son did not have the variant. The identification of the c.2767delC variant further supports the clinical significance of TNPO3 and expands the clinical spectrum of TNPO3-associated LGMD1F.