Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy.

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.

Genetic testing in patients with aortic aneurysms/dissections: a novel genotype/phenotype correlation?

OBJECTIVE: Mutations in the genes encoding fibrillin-1 (FBN1) and transforming growth factor beta receptor type II (TGFBR2) are known causes of Marfan syndrome (MFS) and related disorders. However, a sound correlation between the genotype and the cardiovascular phenotype has not yet been established. The objective of the present study was to identify novel mutations in FBN1 and TGFBR2 and to assess whether the type of mutation is linked to a particular clinical subtype of the cardiovascular condition. METHODS: The clinical records of 36 patients referred to us for molecular genetic diagnosis were reviewed to assess the course and severity of the vascular deterioration. A semiautomatic protocol was established enabling a rapid and cost-effective screening of the genes FBN1 and TGFBR2 by direct sequencing of all coding exons and flanking intronic regions. RESULTS: Novel mutations in FBN1 and TGFBR2 were detected in 12 and 2 patients, respectively. Four individuals carried a recurrent mutation in FBN1. Throughout the study cohort, the incidence of aortic dissections per se did not depend on the type of mutation. However, we found that mutations affecting the calcium-binding epidermal growth factor-like domain were more frequently associated with a dissection of distal parts of the aorta than mutations that lead to a premature termination codon (chi(1)(2): p=0.013), suggesting that the spatio-temporal pattern of vascular deterioration may vary with the type of mutation. CONCLUSIONS: Detecting a mutation in the genes FBN1 and TGFBR2 proves the genetic origin of vascular findings and allows the identification of family members at risk who should undergo preventive checkups. Routine genetic testing of patients with suspected MFS or thoracic aortic aneurysms/dissections could provide further insight into genotype/phenotype correlations related to aortic dissection.

Low-density DNA microarrays are versatile tools to screen for known mutations in hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (HCM or CMH) is a myocardial disorder caused by mutations that affect the contractile machinery of heart muscle cells. Genetic testing of HCM patients is hampered by the fact that mutations in at least eight different genes contribute to the disease. An affordable high-throughput mutation detection method is as yet not available. Since a significant number of mutations have been repeatedly found in unrelated families, we consider it feasible to pre-screen patients for known mutations, before more laborious techniques capable of detecting new mutations are applied. Here we demonstrate that the principle of hybridization of DNA to oligonucleotide probes immobilized on chips (glass slides) can be applied for this purpose. We have developed a low-density oligonucleotide probe array capable of detecting 12 different heterozygous mutations (in four different genes), among them single- and double-base exchanges, a single nucleotide insertion, and a trinucleotide deletion. The assay is simple and may be amenable to automation. Detection is achieved with a CCD camera-based fluorescence biochip reader. The technique turned out to be robust: Variations in either the relative position of a mutation, or the amount and size of target-DNA were compatible with mutation detection. Mutations could even be detected in amplicons as long as 800 bp, allowing the screening of more than one exon in one amplicon. Our data suggest that the development of a chip that covers all or most of known HCM-associated mutations is feasible and useful.