Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death.

Suppressor of lin-12-like-HMG-CoA reductase degradation 1 (SEL1L-HRD1) ER-associated degradation (ERAD) plays a critical role in many physiological processes in mice, including immunity, water homeostasis, and energy metabolism; however, its relevance and importance in humans remain unclear, as no disease variant has been identified. Here, we report a biallelic SEL1L variant (p. Cys141Tyr) in 5 patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. This variant disrupted the formation of a disulfide bond in the luminal fibronectin II domain of SEL1L, largely abolishing the function of the SEL1L-HRD1 ERAD complex in part via proteasomal-mediated self destruction by HRD1. This study reports a disease entity termed ENDI-agammaglobulinemia (ENDI-A) syndrome and establishes an inverse correlation between SEL1L-HRD1 ERAD functionality and disease severity in humans.

Prognostic Value of Genotype-Phenotype Correlations in X-Linked Myotubular Myopathy and the Use of the Face2Gene Application as an Effective Non-Invasive Diagnostic Tool.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy resulting from dysfunction of the protein myotubularin encoded by the MTM1 gene. XLMTM has a high neonatal and infantile mortality rate due to a severe myopathic phenotype and respiratory failure. However, in a minority of XLMTM cases, patients present with milder phenotypes and achieve ambulation and adulthood. Notable facial dysmorphia is also present. METHODS: We investigated the genotype-phenotype correlations in newly diagnosed XLMTM patients in a patients' cohort (previously published data plus three novel variants, n = 414). Based on the facial gestalt difference between XLMTM patients and unaffected controls, we investigated the use of the Face2Gene application. RESULTS: Significant associations between severe phenotype and truncating variants (p < 0.001), frameshift variants (p < 0.001), nonsense variants (p = 0.006), and in/del variants (p = 0.036) were present. Missense variants were significantly associated with the mild and moderate phenotype (p < 0.001). The Face2Gene application showed a significant difference between XLMTM patients and unaffected controls (p = 0.001). CONCLUSIONS: Using genotype-phenotype correlations could predict the disease course in most XLMTM patients, but still with limitations. The Face2Gene application seems to be a practical, non-invasive diagnostic approach in XLMTM using the correct algorithm.

Case Report and Review of the Literature: A New and a Recurrent Variant in the VARS2 Gene Are Associated With Isolated Lethal Hypertrophic Cardiomyopathy, Hyperlactatemia, and Pulmonary Hypertension in Early Infancy.

Mitochondriopathies represent a wide spectrum of miscellaneous disorders with multisystem involvement, which are caused by various genetic changes. The establishment of the diagnosis of mitochondriopathy is often challenging. Recently, several mutations of the VARS2 gene encoding the mitochondrial valyl-tRNA synthetase were associated with early onset encephalomyopathies or encephalocardiomyopathies with major clinical features such as hypotonia, developmental delay, brain MRI changes, epilepsy, hypertrophic cardiomyopathy, and plasma lactate elevation. However, the correlation between genotype and phenotype still remains unclear. In this paper we present a male Caucasian patient with a recurrent c.1168G>A (p.Ala390Thr) and a new missense biallelic variant c.2758T>C (p.Tyr920His) in the VARS2 gene which were detected by whole exome sequencing (WES). VARS2 protein was reduced in the patient's muscle. A resulting defect of oxidative phosphorylation (OXPHOS) was proven by enzymatic assay, western blotting and immunohistochemistry from a homogenate of skeletal muscle tissue. Clinical signs of our patient included hyperlactatemia, hypertrophic cardiomyopathy (HCM) and pulmonary hypertension, which led to early death at the age of 47 days without any other known accompanying signs. The finding of novel variants in the VARS2 gene expands the spectrum of known mutations and phenotype presentation. Based on our findings we recommend to consider possible mitochondriopathy and to include the analysis of the VARS2 gene in the genetic diagnostic algorithm in cases with early manifesting and rapidly progressing HCM with hyperlactatemia.