Front Cover: The cover image is based on the RESEARCH ARTICLE Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial cletiing in humans by Timothy C. Cox et al., https://doi.org/10.1002/humu.23793.

Cover image © Timothy Cox Images.

Ataxia-Telangiectasia-Like Disorder (ATLD) is a rare genomic instability syndrome caused by biallelic variants of MRE11 (meiotic recombination 11) characterized by progressive cerebellar ataxia. We describe the first three French patients with progressive cerebellar ataxia diagnosed with ATLD, associated with compound heterozygosity for unreported MRE11 variants. Functional consequences were evaluated on activation of the ataxia-telangiectasia mutated (ATM) pathway via phosphorylation of ATM targets, but no consistent defect was observed. However, an S-phase checkpoint activation defect after camptothecin was observed in these ATLD patients.

TIMM50 deficiency targets key aspects of mitochondrial physiology, such as the maintenance of mitochondrial morphology, OXPHOS complexes and supercomplexes assembly, and mitochondrial respiratory capacity.

Ataxia-telangiectasia is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated. This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity.

In this study, we use a cohort of solved congenital myasthenic syndrome cases to test methods for variant interpretation with the aid of human phenotype ontology annotations. We show that gene-list filters created from phenotypic annotations perform similarly to curated disease-gene virtual panels, that Exomiser is a valuable aid to variant discovery, and that annotation with over five terms is recommended in our context.

The authors report the identification, via exome sequencing, of segregating variants in two genes, GDF11 and FST (encoding the GDF11 antagonist, Follistatin), in families with cleft lip/palate. The GDF11 variant segregated with both cleft lip/palate, as well as rib and vertebral hypersegmentation, mirroring the Gdf11 knockout mouse, and suggesting a new clefting syndrome, whereas the family harboring the segregating FST variant exhibited isolated cleft lip/palate. Functional assays, together with biochemical, genetic, and expression data support the pathogenicity of the variants and highlight a previously unappreciated role for this pathway in human orofacial development.

Here we report on a patient with severe neurological disease, found to carry biallelic mutations c.683C>T (p.Pro228Leu) and c.871T>G (p.Phe291Val) in the lysyl-tRNA synthetase KARS

Here, we studied the zinc-finger repressor protein ZBTB18 and its disease-associated missense variants reported in subjects diagnosed with microcephaly (N461S, in yellow) and macrocephaly (R495G, in blue). We report that each of these missense ZBTB18 variants (i) influences the DNA-binding specificity of ZBTB18; (ii) its capacity for transcriptional regulation; as well as (iii) its neurodevelopmental signaling activity during cerebral cortex development. Our results suggest that altered transcriptional regulation could represent an important underlying pathological mechanism for missense ZBTB18 variants in cases of brain developmental disorder.

Based upon complementary data from the meta-analysis of 45 disease-causing 5′SS GT>GC variants and the cell culture-based full-length gene splicing analysis of 103 5′SS GT>GC substitutions, we have provided a first estimate of ~15–18% for the proportion of canonical GT 5′SSs that are capable of generating between 1% and 84% normal transcripts in case of the substitution of GT by GC. Given that even the retention of 5% normal transcripts can significantly ameliorate a patient's clinical phenotype, our findings imply the potential existence of hundreds or even thousands of disease-causing 5′SS GT>GC variants that may underlie relatively mild clinical phenotypes. As 5′SS GT>GC variants can also give rise to relatively high levels of wild-type transcripts, our findings imply that 5′SS GT>GC variants may not invariably be pathogenic in disease-causative or disease-associated genes.

Graphical model illustrating the proposed fate of normal and abnormal FKRP proteins.