Novel MYH10 heterozygous variants associated to a syndrome combining mainly ptosis and ocular coloboma expand the MYH10 related phenotypes.

Syndromes associating both eyeball and periocular developmental anomalies, combining iris chorioretinal (ocular) coloboma and ptosis, are described in very rare clinical entities such as Baraitser-Winter cerebrofrontofacial syndrome (BWCFF). We report on six individuals from 3 unrelated families presenting with autosomal dominant eye malformations, including ocular coloboma, ptosis and craniofacial features suggesting BWCFF. However, no neurodevelopmental disorders (NDD) as usually observed in this syndrome were detected.

Copy Number Variation and Epilepsy: State of the Art in the Era of High-Throughput Sequencing-A Multicenter Cohort Study.

Background: Genetic epilepsy diagnosis is increasing due to technological advancements. Although the use of molecular diagnosis is increasing, chromosomal microarray analysis (CMA) remains an important diagnostic tool for many patients. We aim to explore the role and indications of CMA in epilepsy, given the current genomic advances.

Unexpected Inheritance Patterns in a Large Cohort of Patients with a Suspected Ciliopathy.

Ciliopathies are rare genetic disorders caused by dysfunction of the primary or motile cilia. Their mode of inheritance is mostly autosomal recessive with biallelic pathogenic variants inherited from the parents. However, exceptions exist such as uniparental disomy (UPD) or the appearance of a pathogenic variant in of an inherited pathogenic variant.

WGS Revealed Novel Pathogenic Variants, Missed by WES, Causing Ciliary Structure and Function Defects.

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy that affects multiple organs, leading to retinitis pigmentosa, polydactyly, obesity, renal anomalies, cognitive impairment, and hypogonadism. Until now, biallelic pathogenic variants have been identified in at least 24 genes delineating the genetic heterogeneity of BBS. Among those, is a minor contributor to the mutation load and is one of the eight subunits forming the BBSome, a protein complex implied in protein trafficking within the cilia.

The AnnotSV webserver in 2023: updated visualization and ranking.

Much of the human genetics variant repertoire is composed of single nucleotide variants (SNV) and small insertion/deletions (indel) but structural variants (SV) remain a major part of our modified DNA. SV detection has often been a complex question to answer either because of the necessity to use different technologies (array CGH, SNP array, Karyotype, Optical Genome Mapping…) to detect each category of SV or to get an appropriate resolution (Whole Genome Sequencing). Thanks to the deluge of pangenomic analysis, Human geneticists are accumulating SV and their interpretation remains time consuming and challenging.

A Central Role of Telomere Dysfunction in the Formation of a Unique Translocation within the Sub-Telomere Region Resulting in Duplication and Partial Trisomy.

Telomeres play a major role in maintaining genome stability and integrity. Putative involvement of telomere dysfunction in the formation of various types of chromosomal aberrations is an area of active research. Here, we report a case of a six-month-old boy with a chromosomal gain encompassing the 11q22.

Targeted next-generation sequencing in a large series of fetuses with severe renal diseases.

We report the screening of a large panel of genes in a series of 100 fetuses (98 families) affected with severe renal defects. Causative variants were identified in 22% of cases, greatly improving genetic counseling. The percentage of variants explaining the phenotype was different according to the type of phenotype.

A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families.

High prevalence of Bardet-Biedl syndrome in La Réunion Island is due to a founder variant in ARL6/BBS3.

Bardet-Biedl syndrome (BBS) is a rare ciliopathy with variable retinal dystrophy, polydactyly, renal abnormalities, obesity, cognitive impairment, and hypogonadism. Biallelic pathogenic variants have been identified in 24 genes, leading to BBS in an autosomal recessive inheritance pattern. In this study, we investigated a cohort of 16 families (20 individuals) presenting with typical BBS originating from La Réunion Island using sequencing (Sanger and high-throughput methods) and SNP array.

A severe case of Frank-ter Haar syndrome and literature review: Further delineation of the phenotypical spectrum.

Frank-ter Haar syndrome (FTHS) is a rare autosomal recessive syndrome resulting from mutations in the SH3PXD2B gene involved in the formation of podosomes and invadopodia which have a role in extracellular matrix remodelling and cell migration. FTHS is characterized by facial dysmorphism, megalocornea, inconstant glaucoma, variable developmental delay, skeletal and cardiac anomalies. To date, 40 patients have been reported in the literature with a clinical diagnosis of FTHS, only 20 patients having identified mutations.

Novel IQCE variations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish.

Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high-genetic heterogeneity. Among the many genes involved, either in isolated or syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family.

Clinical, histological, and genetic characterization of PYROXD1-related myopathy.

Recessive mutations in PYROXD1, encoding an oxidoreductase, were recently reported in families with congenital myopathy or limb-girdle muscular dystrophy. Here we describe three novel PYROXD1 families at the clinical, histological, and genetic level. Histological analyses on muscle biopsies from all families revealed fiber size variability, endomysial fibrosis, and muscle fibers with multiple internal nuclei and cores.

Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.

Mutations in genes encoding aminoacyl-tRNA synthetases have been reported in several neurological disorders. KARS is a dual localized lysyl-tRNA synthetase and its cytosolic isoform belongs to the multiple aminoacyl-tRNA synthetase complex (MSC). Biallelic mutations in the KARS gene were described in a wide phenotypic spectrum ranging from nonsyndromic deafness to complex impairments.

HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals.

Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues.

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported.

A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi.

Ciliopathies are a group of diseases that affect kidney and retina among other organs. Here, we identify a missense mutation in PIK3R4 (phosphoinositide 3-kinase regulatory subunit 4, named VPS15) in a family with a ciliopathy phenotype. Besides being required for trafficking and autophagy, we show that VPS15 regulates primary cilium length in human fibroblasts, as well as ciliary processes in zebrafish.