Bi-allelic variants in WDR47 cause a complex neurodevelopmental syndrome.

Brain development requires the coordinated growth of structures and cues that are essential for forming neural circuits and cognitive functions. The corpus callosum, the largest interhemispheric connection, is formed by the axons of callosal projection neurons through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps can lead to a range of disorders known as syndromic corpus callosum dysgenesis (CCD).

Arab founder variants: Contributions to clinical genomics and precision medicine.

Background: Founder variants are ancestral variants shared by individuals who are not closely related. The large effect size of some of these variants in the context of Mendelian disorders offers numerous precision medicine opportunities.

Methods: Using one of the largest datasets on Mendelian disorders in the Middle East, we identified 2,908 medically relevant founder variants derived from 18,360 exomes and genomes and investigated their contribution to the clinical annotation of the human genome.

Establishment and characterization of three human pluripotent stem cell lines from Charcot-Marie-Tooth disease Type 4B3 patients bearing mutations in MTMR5/Sbf1 gene.

Myotubularin-Related Protein 5 (MTMR5) is an inactive, poorly characterized D3-phosphatidylinositol phosphatase. Mutations in MTMR5 have been linked to Charcot-Marie-Tooth Disease Type 4B3 (CMT4B3), a rare, early-onset, recessive peripheral neuropathy. Here, we describe the establishment and validation of three human induced pluripotent stem cell (iPSC) lines derived from unrelated CMT4B3 patients, each harboring homozygous MTMR5/Sbf1 mutations.

Biallelic variants in cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.

Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder which is clinically and genetically heterogeneous. Genome sequencing identified biallelic variants in individuals from five unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small and, a more pronounced reduction of, the large mitochondrial ribosomal subunits.

Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders.

Purpose: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.

Methods: We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals.

Clinical and neuroradiological spectrum of biallelic variants in NOTCH3.

Background: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised.

Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells.

Large-scale genomic investigation of pediatric cholestasis reveals a novel hepatorenal ciliopathy caused by PSKH1 mutations.

Purpose: Pediatric cholestasis is the phenotypic expression of clinically and genetically heterogeneous disorders of bile acid synthesis and flow. Although a growing number of monogenic causes of pediatric cholestasis have been identified, the majority of cases remain undiagnosed molecularly.

Methods: In a cohort of 299 pediatric participants (279 families) with intrahepatic cholestasis, we performed exome sequencing as a first-tier diagnostic test.

NanoRanger enables rapid single-base-pair resolution of genomic disorders.

Background: Delineating base-resolution breakpoints of complex rearrangements is crucial for an accurate clinical understanding of pathogenic variants and for carrier screening within family networks or the broader population. However, despite advances in genetic testing using short-read sequencing (SRS), this task remains costly and challenging.

Methods: This study addresses the challenges of resolving missing disease-causing breakpoints in complex genomic disorders with suspected homozygous rearrangements by employing multiple long-read sequencing (LRS) strategies, including a novel and efficient strategy named nanopore-based rapid acquisition of neighboring genomic regions (NanoRanger).

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.

Functional studies in yeast confirm the pathogenicity of a new GINS3 Meier-Gorlin syndrome variant.

Meier-Gorlin syndrome (MGORS) is an autosomal recessive disorder characterized by short stature, microtia, and patellar hypoplasia, and is caused by pathogenic variants of cellular factors involved in the initiation of DNA replication. We previously reported that biallelic variants in GINS3 leading to amino acid changes at position 24 (p.Asp24) cause MGORS.

Human ABL1 deficiency syndrome (HADS) is a recognizable syndrome distinct from ABL1-related congenital heart defects and skeletal malformations syndrome.

Germline gain of function variants in the oncogene ABL1 cause congenital heart defects and skeletal malformations (CHDSKM) syndrome. Whether a corresponding ABL1 deficiency disorder exists in humans remains unknown although developmental defects in mice deficient for Abl1 support this notion. Here, we describe two multiplex consanguineous families, each segregating a different homozygous likely loss of function variant in ABL1.

Clinical exome sequencing by general pediatricians: high clinical utility and no evidence of inappropriate testing.

Background: Genetic disorders account for a large percentage of admissions and outpatient visits to children's hospitals around the world. Clinical exome sequencing (CES) is a valuable diagnostic tool in the workup of these disorders; however, it is not routinely requested by general pediatricians. This may represent a missed opportunity to increase patient access to this powerful diagnostic tool.

Neurodevelopmental disorders associated variants in disrupt the activity of the ADAT2/ADAT3 tRNA deaminase complex and impair neuronal migration.

The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown.

Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications.

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC.

The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

We describe humans with rare biallelic loss-of-function variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ T cell development.