Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects

Slavotinek, Anne; Garcia, Sarah; Chandratillake, Gemma; Bardakjian, Tanya; Ullah, Ehsan; Wu, Di; Umeda, Keiji; Lao, Richard; Tang, Paul Ling-Fung; Wan, Eunice; Madireddy, Lohith; Lyalina, Svetlana; Mendelsohn, Bryce A.; Dugan, Shannon; Tirch, Jeanie; Tischler, R.; Harris, Jason; Clark, Michael J.; Chervitz, Stephen A.; Patwardhan, Amol V.; West, John; Ursell, Philip C.; Campomanes, Alejandra de Alba; Schneider, Adele; Kwok, Pui‐Yan; Baranzini, Sergio E.; Chen, R.O.

doi:10.1111/cge.12543

Cited by 62 publications

(64 citation statements)

References 22 publications

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“…Whereas symptoms in our patient fit the general spectrum of symptoms of malfunctioning RA signalling we did not observe microphthalmia. However, given the refractive error, the measured eyeball dimensions might be somewhat smaller than expected (Discussion section in Appendix S1).…”

Section: Discussionmentioning

confidence: 99%

Syndromic chorioretinal coloboma associated with heterozygous de novo RARA mutation affecting an amino acid critical for retinoic acid interaction

et al. 2019

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Retinoid acid receptors (RAR) are transcription factors that bind retinoic acid (RA), a metabolite of vitamin A. RARs are composed of three subunits encoded by RARA, RARB and RARG. In humans, RARB defects cause syndromic microphthalmia. So far, no germline pathogenic variants have been identified in RARA or RARG. We describe a girl with a de novo mutation NM_000964 c.826C > T (p.Arg276Trp) in RARA with symptoms overlapping those described in RARB patients (coloboma, muscular hypotonia, dilated pulmonary artery, ectopic kidney). RARA Arg276 residue is functionally important, as it was previously shown that its substitution for Ala or Gln causes a 50‐ or 21‐fold impairment of RA binding, respectively. Moreover, in leukemic cells, the p.Arg611Trp mutation in a chimeric PML/RARA gene (corresponding to the RARA p.Arg276Trp detected in our patient) conferred resistance to therapy by decreasing binding of all‐trans RA. The functional effect of RARA p.Arg276Trp was further confirmed by in silico modeling which showed that binding of RA by the Trp276 variant was similarly defective as in the deleterious model Ala276 mutant. We propose that RARA p.Arg276Trp causes the disease by affecting RA interaction with the RARA receptor.

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Section: Discussionmentioning

confidence: 99%

Syndromic chorioretinal coloboma associated with heterozygous de novo RARA mutation affecting an amino acid critical for retinoic acid interaction

et al. 2019

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“…, ; Slavotinek et al. ). In this study, we used WES to examine 47 genes in three unrelated MA families.…”

Section: Introductionmentioning

confidence: 99%

Panel‐based whole exome sequencing identifies novel mutations in microphthalmia and anophthalmia patients showing complex Mendelian inheritance patterns

Riera

Wert

Nieto

et al. 2017

Molec Gen & Gen Med

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BackgroundMicrophthalmia and anophthalmia (MA) are congenital eye abnormalities that show an extremely high clinical and genetic complexity. In this study, we evaluated the implementation of whole exome sequencing (WES) for the genetic analysis of MA patients. This approach was used to investigate three unrelated families in which previous single‐gene analyses failed to identify the molecular cause.MethodsA total of 47 genes previously associated with nonsyndromic MA were included in our panel. WES was performed in one affected patient from each family using the AmpliSeqTM Exome technology and the Ion ProtonTM platform.ResultsA novel heterozygous OTX2 missense mutation was identified in a patient showing bilateral anophthalmia who inherited the variant from a parent who was a carrier, but showed no sign of the condition. We also describe a new PAX6 missense variant in an autosomal‐dominant pedigree affected by mild bilateral microphthalmia showing high intrafamiliar variability, with germline mosaicism determined to be the most plausible molecular cause of the disease. Finally, a heterozygous missense mutation in RBP4 was found to be responsible in an isolated case of bilateral complex microphthalmia.ConclusionThis study highlights that panel‐based WES is a reliable and effective strategy for the genetic diagnosis of MA. Furthermore, using this technique, the mutational spectrum of these diseases was broadened, with novel variants identified in each of the OTX2,PAX6, and RBP4 genes. Moreover, we report new cases of reduced penetrance, mosaicism, and variable phenotypic expressivity associated with MA, further demonstrating the heterogeneity of such disorders.

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“…This patient and her biological parents underwent exome sequencing as part of a larger study involving patients with microphthalmia, anophthalmia and coloboma (MAC; Slavotinek et al, 2015). Libraries were prepared and sequenced on a HiSeq4000 (Illumina, San Diego, CA, USA) according to previously published methods (Slavotinek et al, 2015).…”

Section: Methodsmentioning

confidence: 99%

“…Libraries were prepared and sequenced on a HiSeq4000 (Illumina, San Diego, CA, USA) according to previously published methods (Slavotinek et al, 2015). Variants were assessed for deleteriousness using Sorting Intolerant from Tolerant (SIFT) and PolyPhen-2 databases and mutations that had a SIFT score <0.05 or a PolyPhen-2 score >0.909 were retained.…”

Section: Methodsmentioning

confidence: 99%

Two missense mutations in SALL4 in a patient with microphthalmia, coloboma, and optic nerve hypoplasia

Ullah

Madireddy

et al. 2016

Ophthalmic Genetics

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To investigate the genetic etiology of anophthalmia and microphthalmia, we used exome sequencing in a Caucasian female with unilateral microphthalmia and coloboma, bilateral optic nerve hypoplasia, ventricular and atrial septal defects and growth delays. We found two sequence variants in SALL4 - c.[575C>A], predicting p.(Ala192Glu), that was paternally inherited, and c.[2053G>C], predicting p.(Asp685His), that was maternally inherited. Haploinsufficiency for SALL4 due to nonsense or frameshift mutations has been associated with acro-renal ocular syndrome that is characterized by eye defects including Duane anomaly and coloboma, in addition to radial ray malformations and renal abnormalities. Our report is the first description of structural eye defects associated with two missense variants in SALL4 inherited in trans; the absence of reported findings in both parents suggests that both sequence variants are hypomorphic mutations and that both are needed for the ocular phenotype. Sall4 is expressed in the developing lens and regulates Bmp4, leading us to speculate that altered BMP4 expression was responsible for the eye defects, but we could not demonstrate altered BMP4 expression in vitro after using small interfering RNAs (siRNAs) to reduce SALL4 expression. We conclude that SALL4 hypomorphic variants may influence eye development.

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Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects

Cited by 62 publications

References 22 publications

Syndromic chorioretinal coloboma associated with heterozygous de novo RARA mutation affecting an amino acid critical for retinoic acid interaction

Syndromic chorioretinal coloboma associated with heterozygous de novo RARA mutation affecting an amino acid critical for retinoic acid interaction

Panel‐based whole exome sequencing identifies novel mutations in microphthalmia and anophthalmia patients showing complex Mendelian inheritance patterns

Two missense mutations in SALL4 in a patient with microphthalmia, coloboma, and optic nerve hypoplasia

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