Functional assessment of IDUA variants of uncertain significance identified by newborn screening.

With the expansion of newborn screening efforts for MPS disorders, the number of identified variants of uncertain significance in IDUA continues to increase. To better define functional consequences of identified IDUA variants, we developed a HEK293-based expression platform that can be used to determine the relative specific activity of variant α-iduronidases by combining a fluorescence-based activity assay and semi-quantitative western blotting. We employed the current platform to characterize over thirty different IDUA variants, including known benign and pathogenic variants, as well as multiple variants of uncertain significance identified through newborn screening.

Bifocal retinal degeneration observed on ultra-widefield autofluorescence in some cases of CRX-associated retinopathy.

Background: Variants in CRX are associated with dominantly inherited retinopathy with considerable phenotypic variability. Many patients have central retinal degeneration; in some patients, we have observed an additional focus of degeneration in the nasal retina. This study explores this phenotypic association amongst patients with CRX-associated disease.

Variants in cause a novel oculo-vertebral-renal (OVR) syndrome.

Colobomatous microphthalmia is a potentially blinding congenital ocular malformation that can present either in isolation or together with other syndromic features. Despite a strong genetic component to disease, many cases lack a molecular diagnosis. We describe a novel autosomal dominant oculo-vertebral-renal (OVR) syndrome in six independent families characterized by colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities.

Biallelic Loss-of-Function Variants in UBAP1L and Nonsyndromic Retinal Dystrophies.

Importance: Inherited retinal dystrophies (IRDs) present a challenge in clinical diagnostics due to their pronounced genetic heterogeneity. Despite advances in next-generation sequencing (NGS) technologies, a substantial portion of the genetic basis underlying IRDs remains elusive. Addressing this gap seems important for gaining insights into the genetic landscape of IRDs, which may help improve diagnosis and prognosis and develop targeted therapies in the future.

Bi-allelic variants in COQ8B, a gene involved in the biosynthesis of coenzyme Q10, lead to non-syndromic retinitis pigmentosa.

Retinitis pigmentosa (RP) is a Mendelian disease characterized by gradual loss of vision, due to the progressive degeneration of retinal cells. Genetically, it is highly heterogeneous, with pathogenic variants identified in more than 100 genes so far. Following a large-scale sequencing screening, we identified five individuals (four families) with recessive and non-syndromic RP, carrying as well bi-allelic DNA changes in COQ8B, a gene involved in the biosynthesis of coenzyme Q10.

Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression.

Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.

Investigating Splice Defects in Using Targeted Long-Read Sequencing.

Biallelic variants in are associated with retinitis pigmentosa (RP) and Type 2 Usher Syndrome (USH2), leading to impaired vision and, additionally, hearing loss in the latter. Although the introduction of next-generation sequencing into clinical diagnostics has led to a significant uplift in molecular diagnostic rates, many patients remain molecularly unsolved. It is thought that non-coding variants or variants of uncertain significance contribute significantly to this diagnostic gap.

Non-syndromic retinal dystrophy associated with biallelic variation of SUMF1 and reduced leukocyte sulfatase activity.

Biallelic variants in SUMF1 are associated with multiple sulfatase deficiency (MSD), a rare lysosomal storage disorder typically diagnosed in early infancy or childhood, marked by severe neurodegeneration and early mortality. We present clinical and molecular characterisation of three unrelated patients aged 13 to 58 years with milder clinical manifestations due to SUMF1 disease variants, including two adult patients presenting with apparent non-syndromic retinal dystrophy. Whole genome sequencing identified biallelic SUMF1 variants in all three patients; Patient 1 homozygous for a complex allele c.

Clinical, Ophthalmic, and Genetic Characterization of RPGRIP1-Associated Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy.

Purpose: To present the clinical characteristics, retinal features, natural history, and genetics of RPGRIP1-associated early-onset severe retinal dystrophy (EOSRD)/Leber congenital amaurosis (LCA).

Design: Retrospective case series.

Methods: Review of clinical notes, multimodal retinal imaging, and molecular diagnosis of 18 patients (17 families) with EOSRD/LCA and disease-causing variants in RPGRIP1.

Sex Distributions in Non-ABCA4 Autosomal Macular Dystrophies.

Purpose: We sought to explore whether sex imbalances are discernible in several autosomally inherited macular dystrophies.

Methods: We searched the electronic patient records of our large inherited retinal disease cohort, quantifying numbers of males and females with the more common (non-ABCA4) inherited macular dystrophies (associated with BEST1, EFEMP1, PROM1, PRPH2, RP1L1, and TIMP3). BEST1 cases were subdivided into typical autosomal dominant and recessive disease.

Representation of Women Among Individuals With Mild Variants in ABCA4-Associated Retinopathy: A Meta-Analysis.

Importance: Previous studies indicated that female sex might be a modifier in Stargardt disease, which is an ABCA4-associated retinopathy.

Objective: To investigate whether women are overrepresented among individuals with ABCA4-associated retinopathy who are carrying at least 1 mild allele or carrying nonmild alleles.

Data Sources: Literature data, data from 2 European centers, and a new study.

Distinct Clinical Effects of Two RP1L1 Hotspots in East Asian Patients With Occult Macular Dystrophy (Miyake Disease): EAOMD Report 4.

Purpose: To characterize the clinical effects of two RP1L1 hotspots in patients with East Asian occult macular dystrophy (OMD).

Methods: Fifty-one patients diagnosed with OMD harboring monoallelic pathogenic RP1L1 variants (Miyake disease) from Japan, South Korea, and China were enrolled. Patients were classified into two genotype groups: group A, p.

Unusual OCT findings in a patient with CABP4-associated cone-rod synaptic disorder.

Purpose: Bi-allelic variants in CABP4 are associated with congenital cone-rod synaptic disorder, which has also been classified, electrophysiologically, as incomplete congenital stationary night blindness (iCSNB). We describe clinical findings in a patient who demonstrated an unusual macular optical coherence tomography (OCT) phenotype, not previously reported in this condition.

Methods: Our patient underwent multimodal retinal imaging, international standard full-field ERG testing and whole genome sequencing.

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with , and independent confirmatory evidence has recently been published for four more.

Combining a prioritization strategy and functional studies nominates 5'UTR variants underlying inherited retinal disease.

Background: 5' untranslated regions (5'UTRs) are essential modulators of protein translation. Predicting the impact of 5'UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach of a comprehensive prioritization strategy and functional assays to evaluate 5'UTR variation in two large cohorts of patients with inherited retinal diseases (IRDs).

RBP3-Retinopathy-Inherited High Myopia and Retinal Dystrophy: Genetic Characterization, Natural History, and Deep Phenotyping.

Purpose: To examine the genetic and clinical features and the natural history of RBP3-associated retinopathy.

Design: Multi-center international, retrospective, case series of adults and children, with moleculraly confirmed RBP3-asociated retinopathy.

Methods: The genetic, clinical, and retinal imaging findings, including optical coherence tomography (OCT) and fundus autofluorescence (FAF), were investigated both cross-sectionally and longitudinally.

Clinical and Genetic Characterization of RDH12-Retinal Dystrophy in a South American Cohort.

Purpose: To characterize the largest cohort of individuals with retinol dehydrogenase 12 (RDH12)-retinal dystrophy to date, and the first one from South America.

Design: Retrospective multicenter international study.

Subjects: Seventy-eight patients (66 families) with an inherited retinal dystrophy and biallelic variants in RDH12.

Detailed Clinical, Ophthalmic, and Genetic Characterization of ADGRV1-Associated Usher Syndrome.

Purpose: To present the clinical characteristics, retinal features, natural history, and genetics of ADGRV1-Usher syndrome (USH).

Design: Multicenter international retrospective cohort study.

Methods: Clinical notes, hearing loss history, multimodal retinal imaging, and molecular diagnosis were reviewed.