A Further Case Supporting PDCD6IP as the Gene Responsible for a Neurodevelopmental Disorder With Microcephaly.

of clinical and molecular findings in patients with biallelic variants in PDCD6IP.

Myopathic Ehlers-Danlos Syndrome (mEDS) Related to : Two Novel Families and Literature Review.

Myopathic Ehlers-Danlos syndrome (RmEDS) is an emerging hybrid phenotype that combines connective and muscle tissue abnormalities. It has been associated with variants of the gene, which are known as Ullrich congenital muscular dystrophy-2 (UCMD2; 616470) and Bethlem myopathy-2 (BTHLM2; 616471). Here, we report two splicing mutations of identified in three patients from two unrelated families who present a combination of joint hypermobility and axial, distal, and proximal weakness.

Deletion Testing of the Gene Should Be Part of the Diagnostic Pipeline for Hypomyelinating Leukodystrophy (HLD18).

Hypomyelinating leukodystrophies are a heterogeneous group of disorders characterized by abnormal myelin formation in the central nervous system. Thanks to the increased use of NGS, a growing number of pathogenic single nucleotide variants in have recently been reported to be responsible for hypomyelinating leukodystrophy 18 (HLD18), a rare and severe autosomal recessive form. is a small gene (4 exons and 17 kb) encoding 4-dihydroceramide desaturase, which catalyzes the final step in ceramide biosynthesis.

A Novel Missense Variant in in Three Children with Multiple Pituitary Hormone Deficiency Belonging to Two Unrelated Families and Contribution of Additional and Variant.

Background: Multiple genes can disrupt hypothalamic-pituitary axis development, causing multiple pituitary hormone deficiencies (MPHD). Despite advances in next-generation sequencing (NGS) identifying over 30 key genes, 85% of cases remain unsolved, indicating complex genotype-phenotype correlations and variable inheritance patterns.

Objective: This study aimed to identify the MPHD genetics in three probands from two unrelated families.

Nanopore Sequencing Solves an Elusive Case of Sotos Syndrome.

Sotos syndrome is a rare genetic disorder characterized by distinctive facial features, including a broad and prominent forehead, dolichocephaly, and learning disabilities ranging from mild to severe intellectual impairment. Affected individuals often show overgrowth in height and head circumference over two standard deviations. The syndrome is caused by haploinsufficiency of the NSD1 gene, with no evidence of genetic heterogeneity to date.

Gene prioritisation for enhancing molecular diagnosis in rare skeletal muscle disease cohort.

Background: Inherited rare skeletal muscle diseases cause muscle weakness and wasting of variable severity. Without a molecular diagnosis, patients often endure prolonged diagnostic journeys, leading to delays in appropriate management of the disease. This occurs in approximately 60% of patients with rare diseases.

CDK13-Related Disorder: Novel Insights From A Series of 27 Cases and Recommendations for Clinical Management.

In 2016, Sifrim and colleagues described the first group of patients carrying heterozygous pathogenic variants in CDK13 and sharing major clinical features mainly consisting of congenital heart defects, intellectual disability and peculiar facial features (Congenital Heart Defects, Dysmorphic Facial Features, and Intellectual Developmental Disorder; CHDFIDD, OMIM # 617360). This condition is generally referred to as CDK13-related disorder, and since then other reports have provided further clinical and molecular information. Here we describe a group of 27 previously unreported patients to more accurately profile the clinical spectrum associated with CDK13 variants, disclosing novel associated findings, such as complex craniosynostosis and variable skeletal features (e.

Prion protein promotes copper toxicity in Wilson disease.

Copper (Cu) is a vitally important micronutrient, whose balance between essential and toxic levels requires a tightly regulated network of proteins. Dysfunction in key components of this network leads to the disruption of Cu homeostasis, resulting in fatal disorders such as Wilson disease, which is caused by mutations in the hepatic Cu efflux transporter ATP7B. Unfortunately, the molecular targets for normalizing Cu homeostasis in Wilson disease remain poorly understood.

Novel De Novo RALA Missense Variants Expand the Genotype Spectrum of Hiatt-Neu-Cooper Neurodevelopmental Syndrome.

Background: RALA is a small GTPase from the RAS superfamily implicated in signal transduction and cytoskeletal dynamics. Recently, de novo variants in RALA have been associated with a neurodevelopmental syndrome characterized by intellectual disability (ID), developmental delay (DD), and seizures. So far, only < 12 patients have been reported.

high-content screening reveals miR-429 as a protective molecule in photoreceptor degeneration.

Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous disorders characterized by progressive photoreceptor degeneration and irreversible vision loss. MicroRNAs (miRNAs), a class of endogenous non-coding RNAs with post-transcriptional regulatory properties, are known to play a major role in retinal function, both in physiological and pathological conditions. Given their ability to simultaneously modulate multiple molecular pathways, miRNAs represent promising therapeutic tools for disorders with high genetic heterogeneity, such as IRDs.

Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses.

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.

Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids.

Background: Human cardiac organoids closely replicate the architecture and function of the human heart, offering a potential accurate platform for studying cellular and molecular features of aging cardiomyopathy. Senolytics have shown potential in addressing age-related pathologies but their potential to reverse aging-related human cardiomyopathy remains largely unexplored.

Methods: We employed human iPSC-derived cardiac organoids (hCOs/hCardioids) to model doxorubicin(DOXO)-induced cardiomyopathy in an aged context.

Joint contractures is a recurrent clinical feature of individuals with neurodevelopmental disorder due to FOXP1 likely gene disruptive variants.

Haploinsufficiency of FOXP1 gene is responsible for a neurodevelopmental disorder presenting with intellectual disability (ID), autism spectrum disorder (ASD), hypotonia, mild dysmorphic features, and multiple congenital anomalies. Joint contractures are not listed as a major feature of FOXP1-related disorder. We report five unrelated individuals, each harboring likely gene disruptive de novo FOXP1 variants or whole gene microdeletion, who showed multiple joint contractures affecting at least two proximal and/or distal joints.

Structural variant calling and clinical interpretation in 6224 unsolved rare disease exomes.

Structural variants (SVs), including large deletions, duplications, inversions, translocations, and more complex events have the potential to disrupt gene function resulting in rare disease. Nevertheless, current pipelines and clinical decision support systems for exome sequencing (ES) tend to focus on small alterations such as single nucleotide variants (SNVs) and insertions-deletions shorter than 50 base pairs (indels). Additionally, detection and interpretation of large copy-number variants (CNVs) are frequently performed.

Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies.

CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

Loss of function and reduced levels of sphingolipid desaturase DEGS1 variants are both relevant in disease mechanism.

The last step of ex novo ceramide biosynthesis consists of the conversion of dihydroceramide into ceramide catalyzed by sphingolipid Δ4-desaturase DEGS1. DEGS1 variants were found to be responsible for heterogeneous clinical pictures belonging to the family of hypomyelinating leukodystrophies. To investigate the mechanisms making such variants pathogenic, we designed a procedure for the efficient detection of desaturase activity in vitro using LC-MS/MS and prepared a suitable cell model knocking out DEGS1 in HEK-293T cells through CRISPR-Cas9 genome editing (KO-DES-HEK).

Biallelic loss-of-function variants of SLC12A9 cause lysosome dysfunction and a syndromic neurodevelopmental disorder.

Purpose: Pathogenic variants of FIG4 generate enlarged lysosomes and neurological and developmental disorders. To identify additional genes regulating lysosomal volume, we carried out a genome-wide activation screen to detect suppression of enlarged lysosomes in FIG4 cells.

Methods: The CRISPR-a gene activation screen utilized sgRNAs from the promoters of protein-coding genes.

Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation.

WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities.

DAG1 haploinsufficiency is associated with sporadic and familial isolated or pauci-symptomatic hyperCKemia.

DAG1 encodes for dystroglycan, a key component of the dystrophin-glycoprotein complex (DGC) with a pivotal role in skeletal muscle function and maintenance. Biallelic loss-of-function DAG1 variants cause severe muscular dystrophy and muscle-eye-brain disease. A possible contribution of DAG1 deficiency to milder muscular phenotypes has been suggested.

ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures.

Purpose: ATP2B2 encodes the variant-constrained plasma-membrane calcium-transporting ATPase-2, expressed in sensory ear cells and specialized neurons. ATP2B2/Atp2b2 variants were previously linked to isolated hearing loss in patients and neurodevelopmental deficits with ataxia in mice. We aimed to establish the association between ATP2B2 and human neurological disorders.