Papillon–Lefèvre syndrome (PLS; OMIM 245000) is an autosomal recessive condition characterized by palmoplantar hyperkeratosis and periodontitis. In 1997, the gene locus for PLS was mapped to 11q14-21, and in 1999, variants in the cathepsin C gene (CTSC) were identified as causing PLS. To date, a total of 75 different disease-causing mutations have been published for the CTSC gene. A summary of recurrent mutations identified in Hungarian patients and a review of published mutations is presented in this update. Comparison of clinical features in affected families with the same mutation strongly confirm that identical mutations of the CTSC gene can give rise to multiple different phenotypes, making genotype–phenotype correlations difficult. Variable expression of the phenotype associated with the same CTSC mutation may reflect the influence of other genetic and/or environmental factors. Most mutations are missense (53%), nonsense (23%), or frameshift (17%); however, in-frame deletions, one splicing variant, and one 5′ untranslated region (UTR) mutation have also been reported. The majority of the mutations are located in exons 5–7, which encodes the heavy chain of the cathepsin C protein, suggesting that tetramerization is important for cathepsin C enzymatic activity. All the data reviewed here have been submitted to the CTSC base, a mutation registry for PLS at http://bioinf.uta.fi/CTSCbase/.

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of the motor neurons. To date, 126 genes have been implicated in ALS. Therefore, the heterogenous genetic background of ALS requires comprehensive genetic investigative approaches.MethodsIn this study, DNA from 28 Hungarian ALS patients was subjected to targeted high‐throughput sequencing of the coding regions of three Mendelian ALS genes: FUS, SETX, and C9ORF72.ResultsA novel heterozygous missense mutation (c.791A>G, p.N264S) of the SETX gene was identified in a female patient presenting an atypical ALS phenotype, including adult onset and lower motor neuron impairment. No further mutations were detected in the other Mendelian ALS genes investigated.ConclusionOur study contributes to the understanding of the genetic and phenotypic diversity of motor neuron diseases (MNDs). Our results also suggest that the elucidation of the genetic background of MNDs requires a complex approach, including the screening of both Mendelian and non‐Mendelian genes.

Our results demonstrate that PLS and HMS are phenotypic variants of the same disease and, additionally, exclude the presence of a putative genetic modifier factor within the CTSC gene that is responsible for the development of the two phenotypes. We suggest that this putative genetic modifier factor is located outside the CTSC gene, or alternatively, that the development of the different phenotypes is the consequence of different environmental or lifestyle factors.

BackgroundOculocutaneous albinism (OCA) is a clinically and genetically heterogenic group of pigmentation abnormalities. OCA type IV (OCA4, OMIM 606574) develops due to homozygous or compound heterozygous mutations in the solute carrier family 45, member 2 (SLC45A2) gene. This gene encodes a membrane-associated transport protein, which regulates tyrosinase activity and, thus, melanin content by changing melanosomal pH and disrupting the incorporation of copper into tyrosinase.MethodsHere we report two Hungarian siblings affected by an unusual OCA4 phenotype. After genomic DNA was isolated from peripheral blood of the patients, the coding regions of the SLC45A2 gene were sequenced. In silico tools were applied to identify the functional impact of the newly detected mutations.ResultsDirect sequencing of the SLC45A2 gene revealed two novel, heterozygous mutations, one missense (c.1226G > A, p.Gly409Asp) and one nonsense (c.1459C > T, p.Gln437*), which were present in both patients, suggesting the mutations were compound heterozygous. In silico tools suggest that these variations are disease causing mutations.ConclusionsThe newly identified mutations may affect the transmembrane domains of the protein, and could impair transport function, resulting in decreases in both melanosomal pH and tyrosinase activity. Our study provides expands on the mutation spectrum of the SLC45A2 gene and the genetic background of OCA4.

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The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has revolutionised the therapeutic landscape of chronic lymphocytic leukaemia (CLL). Acquired mutations emerging at position C481 in the BTK tyrosine kinase domain are the predominant genetic alterations associated with secondary ibrutinib resistance. To assess the correlation between disease progression, and the emergence and temporal dynamics of the most common resistance mutation BTK C481S , sensitive (10 À4 ) time-resolved screening was performed in 83 relapsed/refractory CLL patients during single-agent ibrutinib treatment. With a median follow-up time of 40 months, BTK C481S was detected in 48Á2% (40/83) of the patients, with 80Á0% (32/40) of them showing disease progression during the examined period. In these 32 cases, representing 72Á7% (32/44) of all patients experiencing relapse, emergence of the BTK C481S mutation preceded the symptoms of clinical relapse with a median of nine months. Subsequent Bcl-2 inhibition therapy applied in 28/32 patients harbouring BTK C481S and progressing on ibrutinib conferred clinical and molecular remission across the patients. Our study demonstrates the clinical value of sensitive BTK C481S monitoring with the largest longitudinally analysed real-world patient cohort reported to date and validates the feasibility of an early prediction of relapse in the majority of ibrutinib-treated relapsed/refractory CLL patients experiencing disease progression.

Pityriasis rubra pilaris (PRP) is a rare papulosquamous skin disorder, which is phenotypically related to psoriasis. Some familial PRP cases show autosomal dominant inheritance due to CARD14 mutations leading to increased nuclear factor κB (NFκB) activation. Moreover, CARD14 polymorphisms have also been implicated in sporadic PRP. A Hungarian PRP patient with childhood onset disease showing worsening of the symptoms in adulthood with poor therapeutic response underwent genetic screening for the CARD14 gene, revealing four genetic variants (rs117918077, rs2066964, rs28674001, and rs11652075). To confirm that the identified genetic variants would result in altered NFκB activity in the patient, functional studies were carried out. Immunofluorescent staining of the NFκB p65 subunit and NFκB-luciferase reporter assay demonstrated significantly increased NFκB activity in skin samples and keratinocytes from the PRP patient compared to healthy samples. Characterization of the cytokine profile of the keratinocytes and peripheral blood mononuclear cells demonstrated that the higher NFκB activation in PRP cells induces enhanced responses to inflammatory stimuli. These higher inflammatory reactions could not be explained solely by the observed CARD14 or other inflammation-related gene variants (determined by whole exome sequencing). Thus our study indicates the importance of investigations on other genetic factors related to PRP and their further functional characterization to bring us closer to the understanding of cellular and molecular background of disease pathogenesis.

LEOPARD syndrome (LS, OMIM 151100) is a rare monogenic disorder. The name is an acronym of its major features such as multiple lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth and sensorineural deafness. LS develops due to mutations in the protein-tyrosine phosphatase nonreceptor-type 11, PTPN11. Here, we have investigated a 51-year-old Hungarian male patient affected by LS. Direct sequencing of the PTPN11 gene revealed a worldwide recurrent missense mutation (c.836A/G; p.Tyr279Cys), which has been previously identified in 47 LS patients. Comparison of the clinical phenotypes of our patient and the ones reported in the literature demonstrates great phenotypic diversity despite the same genotype.