Citations

Wolf‐Hirschhorn syndrome (WHS) is a microdeletion syndrome characterized by distinctive facial features consisting of “Greek warrior helmet” appearance, prenatal and postnatal growth deficiency, developmental disability, and seizures. This disorder is caused by heterozygous deletions on chromosome 4p16.3 often identified by cytogenetic techniques. Many groups have attempted to identify the critical region within this deletion to establish which genes are responsible for WHS. Herein, clinical whole exome sequencing (WES) was performed on a child with developmental delays, mild facial dysmorphisms, short stature, failure to thrive, and microcephaly, and revealed a de novo frameshift variant, c.1676_1679del (p.Arg559Tfs*38), in WHSC1 (NSD2). While WHSC1 falls within the WHS critical region, individuals with only disruption of this gene have only recently been described in the literature. Loss‐of‐function de novo variations in WHSC1 were identified in large developmental delay, autism, diagnostic, and congenital cardiac cohorts, as well as recent case reports, suggesting that de novo loss‐of‐function WHSC1 variants may be related to disease. These findings, along with our patient suggest that loss‐of‐function variation in WHSC1 may lead to a mild form of Wolf‐Hirschhorn syndrome, and also may suggest that the developmental delays, facial dysmorphisms, and short stature seen in WHS may be due to disruption of WHSC1 gene.

Perineuriomas are rare nerve sheath tumors, divided into intraneural and extraneural (soft tissue) types. Intraneural perineuriomas frequently contain TRAF7 mutations, and rarely, chr22q12 deletions. While chr22q losses can occur in soft tissue perineuriomas, comprehensive high-resolution molecular profiling has not been reported in these tumors and TRAF7 status is unknown. We used whole-exome sequencing and OncoScan single nucleotide polymorphism (SNP) array to evaluate 14 soft tissue perineuriomas. Thirteen cases showed 2 or more chromosomal abnormalities, composed primarily of large deletions. Recurrent chr22q deletions, containing the NF2 locus (n=6) and the previously unreported finding of chr17q deletions, with the NF1 locus (n=4) were frequent events and were mutually exclusive in all but1 case. In addition, 5 cases had varying chr2 deletions; and 4 cases had chr6 deletions. A chr10 deletion (previously reported in the sclerosing variant of soft tissue perineurioma) was observed in one case and another case had chr7 chromothripsis as the sole chromosomal abnormality. No TRAF7 mutations or alterations were identified in any case and no other evaluated gene (MAF<0.0001) had recurrent, deleterious mutations in >2 cases. The molecular genetic profiles showed no association with patient sex, age, tumoral histology or anatomic site. OncoScan SNP array analysis was performed on 10 cases and showed high concordance with the whole exome data, validating the large-scale deletions, duplications, and chr7 chromothripsis findings. In soft tissue perineuriomas, recurrent 22q12 deletions (with NF2) and 17q11 deletions (with NF1) appear to be mutually exclusive events, and alterations in NF1 or NF2 likely contribute to perineurioma pathogenesis, similar to other nerve sheath tumors. Moreover, the lack of TRAF7 mutations in soft tissue perineuriomas indicates divergent pathogenetic mechanisms from those of intraneural perineuriomas.

Background and purposeCACNA1S encodes Cav1.1, a voltage sensor for muscle excitation−contraction coupling, which activates the ryanodine receptor 1 (RYR1) leading to calcium release from the sarcoplasmic reticulum. CACNA1S mutations cause hypokalemic periodic paralysis, malignant hyperthermia and congenital myopathy. RYR1 mutations result in congenital myopathy, malignant hyperthermia and rhabdomyolysis.MethodsThe aim was to describe a novel phenotype associated with a CACNA1S variant at a site previously linked to hypokalemic periodic paralysis.ResultsThe patient presented with fluctuating asymptomatic creatine kinase elevation after an episode of rhabdomyolysis but has no history of periodic paralysis. His muscle biopsy showed core‐like structures occurring mainly in type 2 fibers. He carries a novel Cav1.1 variant (p.Arg528Leu) affecting a highly conserved amino acid. Different mutations at the same location cause hypokalemic periodic paralysis.ConclusionThis case underscores the similarity between the phenotypes caused by mutations in two functionally linked proteins, RYR1 and Cav1.1.

AbstractBackgroundCongenital myopathies due to ryanodine receptor (RYR1) mutations are increasingly identified and correlate with a wide range of phenotypes, most commonly that of malignant hyperthermia susceptibility and central cores on muscle biopsy with rare reports of distal muscle weakness, but in the setting of early onset global weakness.MethodsWe report a case of a patient presenting with childhood onset hand stiffness and adult onset progressive hand weakness and jaw contractures discovered to have two variants in the RYR1 gene.ResultsThe patient manifested with distal upper limb weakness which progressed to involve the distal lower limb, proximal upper limb, as well as the face in addition to limited jaw opening. Creatine kinase was mildly elevated with EMG findings supporting a myopathy. Muscle biopsy showed features consistent with centronuclear myopathy. Whole exome sequencing revealed a novel heterozygous pathogenic variant in RYR1 (c.12315_12328delAGAAATCCAGTTCC, p.Glu4106Alafs*8), and a heterozygous missense variant (c.10648C>T, p.Arg3550Trp) of unknown significance in compound heterozygous state.ConclusionWe expand the spectrum of RYR1‐related myopathy with the description of a novel phenotype in an adult patient presenting with hand weakness and suggest considering RYR1 analysis in the diagnosis of distal myopathies.

ABSTRACTIntroduction: A calpain‐3 (CAPN3) gene heterozygous deletion (c.643_663del21) was recently linked to autosomal dominant (AD) limb‐girdle muscular dystrophy. However, the possibility of digenic disease was raised. We describe 3 families with AD calpainopathy carrying this isolated mutation. Methods: Probands heterozygous for CAPN3 c.643_663del21 were identified by targeted next generation or whole exome sequencing. Clinical findings were collected for probands and families. Calpain‐3 muscle Western blots were performed in 3 unrelated individuals. Results: Probands reported variable weakness in their 40s or 50s, with myalgia, back pain, or hyperlordosis. Pelvic girdle muscles were affected with adductor and hamstring sparing. Creatine kinase was normal to 1,800 U/L, independent of weakness severity. Imaging demonstrated lumbar paraspinal muscle atrophy. Electromyographic findings and muscle biopsies were normal to mildly myopathic. Muscle calpain‐3 expression was reduced. Discussion: This study provides further evidence for AD calpainopathy associated with CAPN3 c.643_663del21. No pathogenic variants in other genes known to cause myopathy were detected. Muscle Nerve 57: 679–683, 2018