Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy.

PURPOSE: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established. METHODS: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease. RESULTS: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration. CONCLUSION: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.

First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery.

A high rate of consanguinity leads to a high prevalence of autosomal recessive disorders in inbred populations. One example of inbred populations is the Arab communities in Israel and the Palestinian Authority. In the Palestinian Authority in particular, due to limited access to specialized medical care, most patients do not receive a genetic diagnosis and can therefore neither receive genetic counseling nor possibly specific treatment. We used whole-exome sequencing as a first-line diagnostic tool in 83 Palestinian and Israeli Arab families with suspected neurogenetic disorders and were able to establish a probable genetic diagnosis in 51% of the families (42 families). Pathogenic, likely pathogenic or highly suggestive candidate variants were found in the following genes extending and refining the mutational and phenotypic spectrum of these rare disorders: ACO2, ADAT3, ALS2, AMPD2, APTX, B4GALNT1, CAPN1, CLCN1, CNTNAP1, DNAJC6, GAMT, GPT2, KCNQ2, KIF11, LCA5, MCOLN1, MECP2, MFN2, MTMR2, NT5C2, NTRK1, PEX1, POLR3A, PRICKLE1, PRKN, PRX, SCAPER, SEPSECS, SGCG, SLC25A15, SPG11, SYNJ1, TMCO1, and TSEN54. Further, this cohort has proven to be ideal for prioritization of new disease genes. Two separately published candidate genes (WWOX and PAX7) were identified in this study. Analyzing the runs of homozygosity (ROHs) derived from the Exome sequencing data as a marker for the rate of inbreeding, revealed significantly longer ROHs in the included families compared with a German control cohort. The total length of ROHs correlated with the detection rate of recessive disease-causing variants. Identification of the disease-causing gene led to new therapeutic options in four families.

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

A previously identified missense mutation in STYXL1 is likely benign.

Based on a homozygous missense variant p.Pro311Ala found in three siblings of a consanguineous family, mutations in the STYXL1 gene were suggested to cause moderate intellectual disability, epilepsy and complex behavioural abnormalities. We have detected this variant via whole exome sequencing in a homozygous state in two families. Segregation analyses in our families and thorough validation in international genetic databases provides evidence that this variant is most likely benign. This is important information for genetic counselling. The role of STYXL1 variants in human disease needs to be established.

Effectiveness of antiepileptic therapy in patients with PCDH19 mutations.

PURPOSE: PCDH19 mutations cause epilepsy and mental retardation limited to females (EFMR) or Dravet-like syndromes. Especially in the first years of life, epilepsy is known to be highly pharmacoresistant. The aim of our study was to evaluate the effectiveness of antiepileptic therapy in patients with PCDH19 mutations. METHODS: We report a retrospective multicenter study of antiepileptic therapy in 58 female patients with PCDH19 mutations and epilepsy aged 2-27 years (mean age 10.6 years). RESULTS: The most effective drugs after 3 months were clobazam and bromide, with a responder rate of 68% and 67%, respectively, where response was defined as seizure reduction of at least 50%. Defining long-term response as the proportion of responders after 12 months of treatment with a given drug in relation to the number of patients treated for at least 3 months, the most effective drugs after 12 months were again bromide and clobazam, with a long-term response of 50% and 43%, respectively. Seventy-four percent of the patients became seizure-free for at least 3 months, 47% for at least one year. SIGNIFICANCE: The most effective drugs in patients with PCDH19 mutations were bromide and clobazam. Although epilepsy in PCDH19 mutations is often pharmacoresistant, three quarters of the patients became seizure-free for at least for 3 months and half of them for at least one year. However, assessing the effectiveness of the drugs is difficult because a possible age-dependent spontaneous seizure remission must be considered.