NGS panel analysis in 24 ectopia lentis patients; a clinically relevant test with a high diagnostic yield

E Overwater; K Floor; D van Beek; K de Boer; T van Dijk; Y Hilhorst-Hofstee; A J M Hoogeboom; K J van Kaam; J M van de Kamp; M Kempers; I P C Krapels; H Y Kroes; B Loeys; S Salemink; C T R M Stumpel; V J M Verhoeven; E Wijnands-van den Berg; J M Cobben; J P van Tintelen; M M Weiss; A C Houweling; A Maugeri

doi:10.1016/j.ejmg.2017.06.005

NGS panel analysis in 24 ectopia lentis patients; a clinically relevant test with a high diagnostic yield

Eur J Med Genet. 2017 Sep;60(9):465-473. doi: 10.1016/j.ejmg.2017.06.005. Epub 2017 Jun 19.

Authors

E Overwater¹, K Floor², D van Beek², K de Boer³, T van Dijk², Y Hilhorst-Hofstee⁴, A J M Hoogeboom⁵, K J van Kaam⁶, J M van de Kamp², M Kempers⁷, I P C Krapels⁶, H Y Kroes⁸, B Loeys⁷, S Salemink⁷, C T R M Stumpel⁹, V J M Verhoeven¹⁰, E Wijnands-van den Berg¹¹, J M Cobben¹², J P van Tintelen¹³, M M Weiss², A C Houweling², A Maugeri²

Affiliations

¹ Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: e.overwater@vumc.nl.
² Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
³ Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands.
⁴ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
⁶ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
⁷ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁸ Department of Clinical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
⁹ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁰ Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹¹ Department of Pediatrics, Medical Center Twente, Enschede, The Netherlands.
¹² Department of Medical Genetics, St George's University Hospital London, London, United Kingdom; Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
¹³ Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

PMID: 28642162
DOI: 10.1016/j.ejmg.2017.06.005

Abstract

Background: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes.

Objective: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL.

Methods: A NGS gene panel was analysed in 24 patients with EL.

Results: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected.

Conclusion: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.

Keywords: ADAMTSL4; Ectopia lentis; FBN1; Gene panel; Next generation sequencing.

MeSH terms

ADAMTS Proteins / genetics
Adolescent
Adult
Aged
Child
Child, Preschool
Ectopia Lentis / diagnosis
Ectopia Lentis / genetics*
False Positive Reactions
Female
Genetic Testing / methods*
Genetic Testing / standards
High-Throughput Nucleotide Sequencing / methods*
High-Throughput Nucleotide Sequencing / standards
Humans
Infant
Male
Middle Aged
Sensitivity and Specificity
Sequence Analysis, DNA / methods*
Sequence Analysis, DNA / standards

Substances

ADAMTSL4 protein, human
ADAMTS Proteins