Biallelic disease-causing variants in the ALPK3 gene were first identified in children presenting with a severe cardiomyopathy. More recently, it was shown that carriers of heterozygous ALPK3 null variants are at risk of developing hypertrophic cardiomyopathy (HCM) with an adult onset. Since the number of reported ALPK3 patients is small, the mutational spectrum and clinical data are not fully described. In this multi-centric study, we described the molecular and clinical spectrum of a large cohort of ALPK3 patients. Genetic testing using targeted next generation sequencing was performed in 16 183 cardiomyopathy index cases. Thirty-six patients carried at least one null ALPK3 variant. The five paediatric patients carried two ALPK3 variants, all presented an HCM phenotype with severe outcomes (one transplantation, one heart failure and one cardiac arrest). The 31 adult patients carried heterozygous variants and the main phenotype was HCM (n = 26/31); including 15% (n = 4) presented with an apical or a concentric form of hypertrophy. Reporting a large cohort of ALPK3 patients, this collaborative work confirmed a strong association with HCM and suggesting his screening in the context of idiopathic HCM.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal-dominant genetic disorder, and mutations in the forkhead box L2 (FOXL2) gene are one of the major genetic causes. As this study shows, there are many patients with BPES who do not have FOXL2 mutations, as the screening results in all family members were negative. Using whole-exome sequence analysis, we discovered another possible mutational cause of BPES in integrin subunit beta 5 (ITGB5). The ITGB5 mutation (c.608T>C, p.Ile203Thr) appears in the base sequence of all BPES+ patients in this family, and it appears to be a three-generation-inherited mutation. It can cause changes in base sequence and protein function, and there may be cosegregation of disease phenotypes. ITGB5 is located on the long arm of chromosome three (3q21.2) and is close to the known pathogenic gene FOXL2 (3q23). This study is the first to report ITGB5 mutations in BPES, and we speculate that it may be directly involved in the pathogenesis of BPES or indirectly through the regulation of FOXL2.

BACKGROUND: Hereditary spherocytosis (HS), a commonly encountered hereditary hemolytic disease, is mostly inherited in an autosomal dominant manner. The clinical manifestations in patients with HS show obvious heterogeneity. Moreover, the sensitivity or specificity of some HS diagnostic tests are not ideal and may easily result in misdiagnosis or missed diagnosis in some patients. The objective of this study was to propose a simple and practical diagnostic protocol, which can contribute to the diagnosis of HS and its differential diagnosis with different types of hemolytic anemia such as thalassemia (THAL), autoimmune hemolytic anemia (AIHA), and glucose-6-phosphate dehydrogenase (G6PD) deficiency, thus, to provide an alternative simple and reliable method for better clinical diagnosis of HS.
METHODS: Through combing our research with existing experimental technologies and studies, we propose a simple and practical protocol for HS diagnosis, which will help clinicians to improve HS diagnosis.
RESULTS: Compared with the existing HS diagnostic protocols, the HS diagnostic protocol we proposed is simpler. In this new protocol, some experimental tests with ideal diagnostic efficiency are added, such as mean reticulocyte volume (MRV), mean sphered cell volume (MSCV), mean corpuscular volume (MCV), in combination with the observation of clinical manifestations, family investigation, routine tests for hemolytic anemia, genetic testing, and other screening tests.
CONCLUSIONS: The HS diagnostic protocol we proposed could improve the clinical practice and efficiency of HS diagnosis.

Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs.

We genetically characterized 22 Swiss patients who had been diagnosed with Stargardt disease after clinical examination. We identified in 11 patients (50%) pathogenic bi-allelic ABCA4 variants, c.1760+2T>C and c.4496T>C being novel. The dominantly inherited pathogenic ELOVL4 c.810C>G p.(Tyr270*) and PRPH2-c.422A>G p.(Tyr141Cys) variants were identified in eight (36%) and three patients (14%), respectively. All patients harboring the ELOVL4 c.810C>G p.(Tyr270*) variant originated from the same small Swiss area, identifying a founder mutation. In the ABCA4 and ELOVL4 cohorts, the clinical phenotypes of \"flecks\", \"atrophy\", and \"bull\"s eye like\" were observed by fundus examination. In the small number of patients harboring the pathogenic PRPH2 variant, we could observe both \"flecks\" and \"atrophy\" clinical phenotypes. The onset of disease, progression of visual acuity and clinical symptoms, inheritance patterns, fundus autofluorescence, and optical coherence tomography did not allow discrimination between the genetically heterogeneous Stargardt patients. The genetic heterogeneity observed in the relatively small Swiss population should prompt systematic genetic testing of clinically diagnosed Stargardt patients. The resulting molecular diagnostic is required to prevent potentially harmful vitamin A supplementation, to provide genetic counseling with respect to inheritance, and to schedule appropriate follow-up visits in the presence of increased risk of choroidal neovascularization.

Recessively inherited limb girdle muscular dystrophy (LGMD) type 2A is the most common LGMD worldwide. Here, we report the first single missense variant in CAPN3 causing dominantly inherited calpainopathy. A 43-year-old proband, his father and two sons were heterozygous for a c.1715G>C p.(Arg572Pro) variant in CAPN3. Affected family members had at least three of the following; muscle pain, a LGMD2A pattern of muscle weakness and wasting, muscle fat replacement on magnetic resonance imaging, myopathic muscle biopsy, and elevated creatine kinase. Total calpain 3 protein expression was 4 ± 3% of normal. In vitro analysis of c.1715G>C and the previously described c.643_663del variant indicated that the mutant proteins lack autolytic and proteolytic activity and decrease the quantity of wild-type CAPN3 protein. Our findings suggest that dominantly inherited calpainopathy is not unique to the previously reported c.643_663del mutation of CAPN3, and that dominantly inherited calpainopathy should be considered for other single variations in CAPN3.

Connexins (Cx) are proteins that form cell-to-cell gap junction channels. A mutation at position 188 in the second extracellular loop (E2) domain of hCx46 has been linked to an autosomal dominant zonular pulverulent cataract. As it is dominantly inherited, it is possible that the mutant variant affects the co-expressed wild-type Cx and/or its interaction with other cellular components. Here, we proposed to use concatenated hCx46wt-hCx46N188T and hCx46N188T-hCx46wt to analyze how hCx46N188T affected co-expressed hCx46wt to achieve a dominant inheritance. Heterodimer hCx46wt-hCx46N188T formed fewer gap junction plaques compared to homodimer hCx46wt-hCx46wt, while the hCx46N188T-hCx46N188T homodimer formed almost no gap junction plaques. Dye uptake experiments showed that hemichannels of concatenated variants were similar to hemichannels of monomers. Molecular dynamics simulations revealed that for docking, the N188 of a protomer was engaged in hydrogen bonds (HBs) with R180, N189, and D191 of the counterpart protomer of the adjacent hemichannel. T188 suppressed the formation of HBs between protomers. Molecular dynamics simulations of an equimolar hCx46wt/hCx46N188T gap junction channel revealed a reduced number of HBs between protomers, suggesting reduction of gap junction channels between lens fibers co-expressing the variants.

OBJECTIVE: To report a kindred with an association between hereditary primary lateral sclerosis (PLS) and progressive nonfluent aphasia.
METHODS: Six members from a kindred with 15 affected individuals spanning three generations, suffered from spasticity without muscle atrophy or fasciculation, starting in the lower limbs and spreading to the upper limbs and bulbar musculature, followed by effortful speech, nonfluent language and dementia, in 5 deceased members. Disease onset was during the sixth decade of life, or later. Cerebellar ataxia was the inaugural manifestation in two patients, and parkinsonism, in another.
RESULTS: Neuropathological examination in two patients demonstrated degeneration of lateral corticospinal tracts in the spinal cord, without loss of spinal, brainstem, or cerebral motor neurons. Greater loss of corticospinal fibers at sacral and lumbar, rather than at cervical or medullary levels was demonstrated, supporting a central axonal dying-back pathogenic mechanism. Marked reduction of myelin and nerve fibers in the frontal lobes was also present. Argyrophilic grain disease and primary age-related tauopathy were found in one case each, and considered incidental findings. Genetic testing, including exome sequencing aimed at PLS, ataxia, hereditary spastic paraplegia, and frontotemporal lobe dementia, triplet-repeated primed polymerase chain reaction aimed at dominant spinocerebellar ataxias, and massive sequencing of the human genome, yielded negative results.
CONCLUSIONS: A central distal axonopathy affecting the corticospinal tract, exerted a pathogenic role in the dominantly inherited PLS-progressive nonfluent aphasia association, described herein. Further molecular studies are needed to identify the causative mutation in this disease.

We present here a Finnish nemaline myopathy family with a dominant mutation in the skeletal muscle α-actin gene, p.(Glu85Lys), segregating in three generations. The index patient, a 5-year-old boy, had the typical form of nemaline myopathy with congenital muscle weakness and motor milestones delayed but reached, while his mother never had sought medical attention for her very mild muscle weakness, and his maternal grandmother had been misdiagnosed as having myotonic dystrophy. This illustrates the clinical variability in nemaline myopathy.

Dyslexia is a heritable neurodevelopmental disorder characterized by difficulties in reading and writing. In this study, we describe the identification of a set of 17 polymorphisms located across 1.9Mb region on chromosome 5q31.3, encompassing genes of the PCDHG cluster, TAF7, PCDH1 and ARHGAP26, dominantly inherited with dyslexia in a multi-incident family. Strikingly, the non-risk form of seven variations of the PCDHG cluster, are preponderant in the human lineage, while risk alleles are ancestral and conserved across Neanderthals to non-human primates. Four of these seven ancestral variations (c.460A>C [p.Ile154Leu], c.541G>A [p.Ala181Thr], c.2036G>C [p.Arg679Pro] and c.2059A>G [p.Lys687Glu]) result in amino acid alterations. p.Ile154Leu and p.Ala181Thr are present at EC2: EC3 interacting interface of γA3-PCDH and γA4-PCDH respectively might affect trans-homophilic interaction and hence neuronal connectivity. p.Arg679Pro and p.Lys687Glu are present within the linker region connecting trans-membrane to extracellular domain. Sequence analysis indicated the importance of p.Ile154, p.Arg679 and p.Lys687 in maintaining class specificity. Thus the observed association of PCDHG genes encoding neural adhesion proteins reinforces the hypothesis of aberrant neuronal connectivity in the pathophysiology of dyslexia. Additionally, the striking conservation of the identified variants indicates a role of PCDHG in the evolution of highly specialized cognitive skills critical to reading.