Jul 2026· European Journal of Human Genetics· 1 citation· ⚡ 1 influential· 67 references
Medicine
TL;DR
It is demonstrated that short-read WGS significantly improves diagnostic yield in patients with congenital eye malformations, including those previously undiagnosed despite NGS panel testing.
Abstract
Congenital eye malformations represent a clinically and genetically heterogeneous group of disorders. Despite advances in genetic testing, fewer than half of affected patients receive a definitive molecular diagnosis. However, obtaining a molecular diagnosis is crucial for these patients and their families. Whole genome sequencing (WGS) is now standard practice in the genetic investigation of patients, but its contribution has not been extensively evaluated in patients with ocular malformations. In this work, we performed short-read WGS in a cohort of 100 families presenting with eye developmental disorders, including microphthalmia-anophthalmia spectrum (M/A), coloboma, anterior segment dysgenesis, congenital cataracts and/or foveal hypoplasia. Prior to WGS, 47 individuals had undergone targeted next-generation sequencing (NGS) of genes panels related to ocular development, 11 had chromosomal microarray analysis (CGH-array) and 20 had a combination of both. None had received a definitive genetic diagnosis. WGS identified a (likely) pathogenic variant in eighteen patients. In addition, candidate variants of uncertain significance were detected in nine patients. Notably, fourteen of these variants would have been missed by conventional genes panels or CGH-array, underscoring the broader diagnostic scope of WGS. Our findings demonstrate that short-read WGS significantly improves diagnostic yield in patients with congenital eye malformations, including those previously undiagnosed despite NGS panel testing. These results support the integration of WGS in the genetic evaluation of ocular developmental disorders.
The findings highlight the importance of detailed phenotyping, breakpoint analysis, and segregation studies in interpreting CNVs, particularly VUS and rare intragenic disruptions.
This study provides the first systematic, mutational-level characterization of a Cypriot Mendelian disease cohort, establishing a local baseline diagnostic yield and revealing a high proportion of novel variants that reflect the underrepresentation of Eastern Mediterranean populations in global databases.
A. Theodosiou, L. Kousoulidou, Ioannis Papaevripidou et al.· Genes· 0 citations
The results further demonstrate the genetic heterogeneity of MAC, while supporting the involvement of complex inheritance and/or environmental factors in many of the cases.
Yakov Rabinovich, Y. Vardizer, Shirley Pincovich et al.· Biomolecules· 0 citations
Background: Genetic eye diseases (GEDs) comprise a heterogeneous group of hereditary and de novo disorders that involve all ocular structures, including the retina, optic nerve, vitreous, anterior segment, and ocular development. Their marked clinical and genetic heterogeneity frequently delays diagnosis and access to genetic counseling, multidisciplinary management, and emerging gene-based therapies. Although ophthalmic deep phenotyping remains essential, we propose an approach that prioritizes genetic analysis, particularly in under-resourced healthcare settings with limited access to advanced imaging and electrophysiological tests. Methods: We conducted a retrospective observational study of 101 consecutive patients with suspected genetic eye diseases. All were evaluated at a tertiary referral center in northeastern Mexico between January 2020 and August 2023 through comprehensive ophthalmologic examination supplemented by optical coherence tomography, visual-field testing, and fundus photography when clinically indicated. All patients were offered early molecular testing while awaiting future tests, such as electrophysiological testing or further referral visits. Molecular testing consisted of an ophthalmology-focused next-generation sequencing multigene panel. Results: The primary outcome was molecular diagnostic yield. A clinically actionable molecular diagnosis was established in 45 patients, corresponding to an overall molecular diagnostic yield of 44.6%. A total of 165 variants were identified, including 70 pathogenic, 16 likely pathogenic, 43 variants of uncertain significance, and 36 likely benign variants. Usher syndrome was the most frequent molecular diagnosis (10/45, 22.2%), comprising nine patients with USH2A-associated Usher syndrome type 2 and one patient with MYO7A-associated Usher syndrome type 1B, followed by Stickler syndrome (8/45, 17.8%), oculocutaneous albinism (3/45, 6.7%), and Alström syndrome (2/45, 4.4%). Autosomal recessive disorders represented the predominant inheritance pattern (68.9%). Conclusions: Our findings support ophthalmology-focused multigene panels as an effective first-line diagnostic strategy for patients with suspected genetic eye diseases. Early molecular testing may shorten the diagnostic odyssey, optimize resource utilization, facilitate precision diagnosis and genetic counseling, and guide future targeted deep phenotypic evaluation, prognosis, and eligibility for emerging gene-specific therapies.
M. Ibarra-Ramírez, Jibran Mohamed-Noriega, Joel Arenas-Estala et al.· Genes· 0 citations
Background/Objectives: To describe the genetic resolution rate, molecular findings, and genotype–phenotype correlations of non-ABCA4 and non-BEST1 inherited macular dystrophies (IMDs) within an Irish inherited retinal disease (IRD) registry. Methods: Retrospective review of individuals with a clinical diagnosis of macular or cone dystrophy. Comprehensive phenotyping (dilated ocular biomicroscopy, multimodal retinal imaging, visual electrophysiology) and genetic testing (panel-based next-generation sequencing, single-gene testing, whole exome/genome sequencing, WES/WGS). Variants were interpreted using ACMG AMP criteria, and genotype-phenotype match was confirmed through multidisciplinary review. Results: 232 patients with macular/cone dystrophies were identified. ABCA4 and BEST1 accounted for most molecular diagnoses (47.4%). Removing ABCA4 and BEST1, 59.0% of IMDs were genetically unresolved, higher than the rate in general IRD cohorts. Deep phenotyping enabled diagnostic reclassification in 13/72 (18.1%), namely achromatopsia, congenital stationary night blindness, and oculocutaneous albinism. Further genetic testing resolved 35/72 (48.6%) of those unresolved on first-line testing, with PRPH2 being most prevalent (n = 12), followed by GUCY2D, CRB1, PROM1, and CRX. Characteristic phenotypic signatures—such as CRB1-associated retinal thickening and retinoschisis or PROM1-associated Stargardt-like changes—supported known genotype–phenotype correlations. Conclusions: Genetic resolution rates for rare IMDs remain lower than pan-retinal IRD phenotypes. Beyond ABCA4 and BEST1, IMDs exhibit substantial genetic and phenotypic heterogeneity (24 genotypes in this cohort), with low molecular diagnostic rates despite comprehensive sequencing approaches. Detailed multimodal phenotyping (i.e., structural, functional and extra-ocular) is essential to refine diagnosis, guide genetic testing and interpret candidate variants. Genetic testing is challenging when the retinal phenotype is advanced (i.e., atrophy) or lacks pathognomonic features. Meticulous phenotyping (functional, structural and systemic) and broader genomic strategies (e.g., WES/WGS) may further increase diagnostic yield, though gene panel content is constantly improving. Consistently improving molecular diagnostic rates will ensure equitable access to emerging gene-specific therapies.
Deirdre A Harford, Marcus Conway, Bridget Moran et al.· Genes· 0 citations
Inherited peripheral neuropathies (IPNs) comprise a clinically and genetically heterogeneous group of disorders affecting approximately 1 in 2500 individuals and represent one of the most common inherited neurologic diseases. The rapidly expanding identification of disease-causing genes and the widespread implementation of next-generation sequencing (NGS) have fundamentally transformed the diagnostic evaluation of these disorders. Contemporary molecular testing has substantially increased diagnostic yield, shortened the diagnostic delay, refined disease classification, and strengthened genotype-phenotype correlations. In the United States, NGS-based multigene panels have become the most cost-effective first-line molecular diagnostic approach for most patients with suspected inherited neuropathies, whereas phenotype-directed single-gene testing remains appropriate in selected clinical circumstances and in healthcare systems in which access to comprehensive sequencing is limited. Despite these advances, challenges continue to affect diagnostic accuracy, including interpretation of variants of uncertain significance, detection of copy number variants and repeat expansions, technical limitations associated with highly homologous genomic regions such as SORD, and variability in gene content and analytic performance among commercially available testing platforms. Accurate diagnosis therefore requires integration of clinical phenotype, electrodiagnostic findings, family history, and molecular data. Establishing a precise genetic diagnosis has become increasingly important because it improves prognostic accuracy, guides genetic counseling and cascade testing, identifies patients with treatable hereditary neuropathies such as transthyretin amyloidosis, and facilitates enrollment in gene-specific clinical trials and emerging precision therapies. An evidence-based, phenotype-driven approach that incorporates contemporary molecular technologies is essential to maximize diagnostic efficiency while recognizing the strengths and limitations of currently available genetic testing strategies.
M. Saporta· Muscle and Nerve· 0 citations
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