Identification of novel pathogenic variants and novel gene-phenotype correlations in Mexican subjects with microphthalmia and/or anophthalmia by next-generation sequencing

Matías-Pérez, Diana; García-Montaño, Leopoldo A; Cruz‐Aguilar, Marisa; García-Montalvo, Iván Antonio; Nava-Valdéz, Jessica; Barragán-Arévalo, Tania; Villanueva‐Mendoza, Cristina; Villarroel, Camilo E.; Guadarrama-Vallejo, Clavel; Cruz, Rocío Villafuerte-de la; Chacón‐Camacho, Oscar F.; Zenteno, Juan Carlos

doi:10.1038/s10038-018-0504-1

Cited by 20 publications

(16 citation statements)

References 64 publications

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“…This data was analyzed prioritizing 83 known A/M genes and resulted in the identification of causative mutations in 3 individuals (11%). More recently, WES was applied to a cohort of 14 patients with bilateral A/M (Matias-Perez et al 2018). As expected, given the bilaterality and severity of ocular phenotype, the mutation detection rate in this cohort was almost 60% (8/14), the majority carrying alterations in well-known eye genes (7/8).…”

Section: -Diagnostic Strategysupporting

confidence: 52%

“…Thus, WES studies resulted in a detection rate similar to that obtained by the targeted sequencing of a panel of the main known genes. However, an advantage of WES over panel sequencing is the opportunity to identify new causal genes in particular pedigrees (Chassaing et al 2016b;Matias-Perez et al 2018;Patel et al 2018;Srour et al 2013).…”

Section: -Diagnostic Strategymentioning

confidence: 99%

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Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

et al. 2019

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Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause ocular growth and structural defects, such as anophthalmia and microphthalmia (A/M). A/M can be isolated or occur with systemic anomalies, when they may form part of a recognizable syndrome. Their etiology includes genetic and environmental factors; several hundred genes involved in ocular development have been identified in humans or animal models. In humans, around 30 genes have been repeatedly implicated in A/M families, although many other genes have been described in single cases or families, and some genetic syndromes include eye anomalies occasionally as part of a wider phenotype. As a result of this broad genetic heterogeneity, with one or two notable exceptions, each gene explains only a small percentage of cases. Given the overlapping phenotypes, these genes can be most efficiently tested on panels or by whole exome/genome sequencing for the purposes of molecular diagnosis. However, despite whole exome/genome testing more than half of patients currently remain without a molecular diagnosis. The proportion of undiagnosed cases is even higher in those individuals with unilateral or milder phenotypes. Furthermore, even when a strong gene candidate is available for a patient, issues of incomplete penetrance and germinal mosaicism make diagnosis and genetic counselling challenging. In this review, we present the main genes implicated in nonsyndromic human A/M phenotypes and, for practical purposes, classify them according to the most frequent or predominant phenotype each is associated with. Our intention is that this will allow clinicians to rank and prioritize their molecular analyses and interpretations according to the phenotypes of their patients.

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Section: -Diagnostic Strategysupporting

confidence: 52%

Section: -Diagnostic Strategymentioning

confidence: 99%

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

et al. 2019

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“…Our yield of pathogenic variants (1/19; 5%) was much lower than two recent studies employing WES in patients with anophthalmia and microphthalmia (60%) 29 and in microphthalmia and posterior microphthalmia (61%) 1 . However, low rates of diagnosis have previously been reported in patients with MAC who underwent exome sequencing (11%) 30 .…”

Section: Resultscontrasting

confidence: 64%

“…19 T A B L E 1 Ocular findings in 19 patients with structural eye defects, together with exome results ginal retina by downregulating the expression of proneural genes. [20][21][22] The gene is an excellent candidate for structural eye defects and the variant had a CADD score of 33, but heterozygosity for this WNT2B Our yield of pathogenic variants (1/19; 5%) was much lower than two recent studies employing WES in patients with anophthalmia and microphthalmia (60%) 29 and in microphthalmia and posterior microphthalmia (61%). 1 However, low rates of diagnosis have previously been reported in patients with MAC who underwent exome sequencing (11%).…”

Section: Methodsmentioning

confidence: 70%

Exome sequencing in patients with microphthalmia, anophthalmia, and coloboma (MAC) from a consanguineous population

Islam¹,

Htun

Lai

et al. 2020

Clinical Genetics

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Next-generation sequencing strategies have resulted in mutation detection rates of 21% to 61% in small cohorts of patients with microphthalmia, anophthalmia and coloboma (MAC), but despite progress in identifying novel causative genes, many patients remain without a genetic diagnosis. We studied a cohort of 19 patients with MAC who were ascertained from a population with high rates of consanguinity. Using single nucleotide polymorphism (SNP) arrays and whole exome sequencing (WES), we identified one pathogenic variant in TENM3 in a patient with cataracts in addition to MAC. We also detected novel variants of unknown significance in genes that have previously been associated with MAC, including KIF26B, MICU1 and CDON, and identified variants in candidate genes for MAC from the Wnt signaling pathway, comprising LRP6, WNT2B and IQGAP1, but our findings do not prove causality. Plausible variants were not found for many of the cases, indicating that our current understanding of the pathogenesis of MAC, a highly heterogeneous group of ocular defects, remains incomplete.

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“…2b ). This recently reported 10 p.Gly212Ser variant affects a key glycine (G-X-Y) residue of the COL4A1 protein and is expected to disrupt collagen IV heterotrimer formation with COL4A2, as noted for other missense pathogenic COL4A1 variants associated with ASD (Fig. 3a ).…”

Section: Resultsmentioning

confidence: 71%

Revealing hidden genetic diagnoses in the ocular anterior segment disorders

Yousoof

Grigg

et al. 2020

Genetics in Medicine

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Purpose: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion. Methods: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases. Results: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6. Conclusions: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.

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Identification of novel pathogenic variants and novel gene-phenotype correlations in Mexican subjects with microphthalmia and/or anophthalmia by next-generation sequencing

Cited by 20 publications

References 64 publications

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

Exome sequencing in patients with microphthalmia, anophthalmia, and coloboma (MAC) from a consanguineous population

Revealing hidden genetic diagnoses in the ocular anterior segment disorders

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