GPATCH11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment.

Here we conduct a study involving 12 individuals with retinal dystrophy, neurological impairment, and skeletal abnormalities, with special focus on GPATCH11, a lesser-known G-patch domain-containing protein, regulator of RNA metabolism. To elucidate its role, we study fibroblasts from unaffected individuals and patients carrying the recurring c.328+1 G > T mutation, which specifically removes the main part of the G-patch domain while preserving the other domains.

Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans.

Ocular coloboma (OC) is a congenital disorder caused by the incomplete closure of the embryonic ocular fissure. OC can present as a simple anomaly or, in more complex forms, be associated with additional ocular abnormalities. It can occur in isolation or as part of a broader syndrome, exhibiting considerable genetic heterogeneity.

Four Unique Genetic Variants in Three Genes Account for 62.7% of Early-Onset Severe Retinal Dystrophy in Chile: Diagnostic and Therapeutic Consequences.

Leber congenital amaurosis (LCA)/early-onset severe retinal dystrophy (EOSRD) stand as primary causes of incurable childhood blindness. This study investigates the clinical and molecular architecture of syndromic and non-syndromic LCA/EOSRD within a Chilean cohort (67 patients/60 families). Leveraging panel sequencing, 95.

PCDH12 loss results in premature neuronal differentiation and impeded migration in a cortical organoid model.

Protocadherins (PCDHs) are cell adhesion molecules that regulate many essential neurodevelopmental processes related to neuronal maturation, dendritic arbor formation, axon pathfinding, and synaptic plasticity. Biallelic loss-of-function variants in PCDH12 are associated with several neurodevelopmental disorders (NDDs). Despite the highly deleterious outcome resulting from loss of PCDH12, little is known about its role during brain development and disease.

Autosomal recessive pathogenic MSTO1 variants in hereditary optic atrophy.

Gerber et al report 2 autosomal recessive pathogenic Misato homolog 1 (MSTO1) variants causing hereditary optic atrophy and raise concerns about a previously identified dominant variant of MSTO1 by Gal et al (2017).

Autosomal recessive Leber hereditary optic neuropathy, a new neuro-ophthalmo-genetic paradigm.

Leber hereditary optic neuropathy (LHON) is a primary inherited neurodegenerative disorder of the optic nerve. It has been ascribed to variants in the mitochondrial genome, mainly the m.3460G>A, m.

Association of Missense Variants in VSX2 With a Peculiar Form of Congenital Stationary Night Blindness Affecting All Bipolar Cells.

Importance: Congenital stationary night blindness (CSNB) is an inherited stationary retinal disorder that is clinically and genetically heterogeneous. To date, the genetic association between some cases with CSNB and an unusual complex clinical picture is unclear.

Objective: To describe an unreported CSNB phenotype and the associated gene defect in 3 patients from 2 unrelated families.

Bi-allelic variants in disrupt the development of multiple organs in humans.

Background: Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects delineate the PDAC syndrome. We aim to identify the cause of PDAC syndrome in patients who do not carry pathogenic variants in and , which have been previously associated with this disorder.

Methods: We sequenced the exome of patients with unexplained PDAC syndrome and performed functional validation of candidate variants.

Expanding the KIF4A-associated phenotype.

Kinesin super family (KIF) genes encode motor kinesins, a family of evolutionary conserved proteins, involved in intracellular trafficking of various cargoes. These proteins are critical for various physiological processes including neuron function and survival, ciliary function and ciliogenesis, and cell-cycle progression. Recent evidence suggests that alterations in motor kinesin genes can lead to a variety of human diseases, including monogenic disorders.

Congenital Microcoria: Clinical Features and Molecular Genetics.

Iris integrity is required to regulate both the amount of light reaching the retina and intraocular pressure (IOP), with elevated IOP being a major risk factor for glaucoma. Congenital microcoria (MCOR) is an extremely rare, autosomal dominant disease affecting iris development and hindering both of these functions. It is characterized by absent or underdeveloped dilator muscle fibers and immaturity of the iridocorneal angle-where the aqueous humor is drained-which play a central role in IOP regulation.

Mutations Cause Nuclear LHON-like Optic Neuropathy.

Pathological variants in the nuclear malonyl-CoA-acyl carrier protein transacylase () gene, which encodes a mitochondrial protein involved in fatty-acid biogenesis, have been reported in two siblings from China affected by insidious optic nerve degeneration in childhood, leading to blindness in the first decade of life. After analysing 51 families with negative molecular diagnostic tests, from a cohort of 200 families with hereditary optic neuropathy (HON), we identified two novel mutations in a female patient who presented with acute, sudden, bilateral, yet asymmetric, central visual loss at the age of 20. This presentation is consistent with a Leber hereditary optic neuropathy (LHON)-like phenotype, whose existence and association with and has only recently been described.

Whole Locus Sequencing Identifies a Prevalent Founder Deep Intronic Pathologic Variant in the French Leber Congenital Amaurosis Cohort.

Leber congenital amaurosis (LCA) encompasses the earliest and most severe retinal dystrophies and can occur as a non-syndromic or a syndromic disease. Molecular diagnosis in LCA is of particular importance in clinical decision-making and patient care since it can provide ocular and extraocular prognostics and identify patients eligible to develop gene-specific therapies. Routine high-throughput molecular testing in LCA yields 70%-80% of genetic diagnosis.

YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations.

Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy.

Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement.

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual.

Genetic Deciphering of Early-Onset and Severe Retinal Dystrophy Associated with Sensorineural Hearing Loss.

The specific association of Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (LCA-like) with sensorineural hearing loss (SHL) is uncommon. Recently, we ascribed some of these distinctive associations to dominant and de novo mutations in the β-tubulin 4B isotype-encoding gene (TUBB4B), providing a link between a sensorineural disease and anomalies in microtubules behavior. Here, we report 12 sporadic cases with LCA/SHL or LCA-like/SHL and no TUBB4B mutation.

Description of Two Siblings with Apparently Severe CEP290 Mutations and Unusually Mild Retinal Disease Unrelated to Basal Exon Skipping or Nonsense-Associated Altered Splicing.

CEP290 mutations cause a spectrum of ciliopathies, including Leber congenital amaurosis. Milder retinal diseases have been ascribed to exclusion of CEP290 mutant exons through basal exon skipping (BES) and/or nonsense-associated altered splicing (NAS). Here, we report two siblings with some preserved vision despite biallelism for presumably severe CEP290 mutations: a maternal splice site change in intron 18 (c.

Genetic architecture of retinoic-acid signaling-associated ocular developmental defects.

Ocular developmental anomalies are among the most common causes of severe visual impairment in newborns (combined incidence 1-2:10,000). They comprise a wide range of inborn errors of eye development with a spectrum of overlapping phenotypes and they are frequently associated with extraocular malformations, neuropsychomotor developmental delay and/or intellectual disabilities. Many studies from model organisms have demonstrated the role of retinoic acid (RA) during organogenesis, including eye development, and have revealed the wide spectrum of malformations that can arise from defective RA signaling.