Genome-wide linkage and haplotype sharing analysis implicates the MCDR3 locus as a candidate region for a developmental macular disorder in association with digit abnormalities

ABSTRACT

Background: Developmental macular disorders are a heterogeneous group of rare retinal conditions that can cause significant visual impairment from childhood. Among these disorders, autosomal dominant North Carolina macular dystrophy (NCMD) has been mapped to 6q16 (MCDR1) with recent support for a non-coding disease mechanism of PRDM13. A second locus on 5p15-5p13 (MCDR3) has been implicated in a similar phenotype, but the disease-causing mechanism still remains unknown.

Methods: Two families affected by a dominant developmental macular disorder that closely resembles NCMD in association with digit abnormalities were included in the study. Family members with available DNA were genotyped using the Affymetrix GeneChip Human Mapping 250K Sty array. A parametric multipoint linkage analysis assuming a fully penetrant dominant model was performed using MERLIN. Haplotype sharing analysis was carried out using the non-parametric Homozygosity Haplotype method. Whole-exome sequencing was conducted on selected affected individuals.

Results: Linkage analysis excluded MCDR1 from the candidate regions (LOD < –2). There was suggestive linkage (LOD = 2.7) at two loci, including 9p24.1 and 5p15.32 that overlapped with MCDR3. The haplotype sharing analysis in one of the families revealed a 5 cM shared IBD segment at 5p15.32 (p value = 0.004). Whole-exome sequencing did not provide conclusive evidence for disease-causing alleles.

Conclusions: These findings do not exclude that this phenotype may be allelic with NCMD MCDR3 at 5p15 and leave the possibility of a non-coding disease mechanism, in keeping with recent findings on 6q16. Further studies, including whole-genome sequencing, may help elucidate the underlying genetic cause of this phenotype and shed light on macular development and function.

KEYWORDS:

• Congenital limb deformities
• genetic linkage
• macular dystrophy, retinal 1, human
• North Carolina macular dystrophy
• retinal dysplasia

Acknowledgments

We thank Dr. Thomas Scerri and Prof. Melanie Bahlo for their help with the use of LINKDATAGEN and Dr. Vincent Plagnol for his help with the whole-exome sequencing data analysis.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Funding

This work was supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust and UCL Institute of Ophthalmology (UK), Fight for Sight including the Mercer Fund (UK), the Macular Society (UK), Moorfields Eye Hospital Special Trustees (UK), Moorfields Eye Charity (UK), the Foundation Fighting Blindness (FFB; USA), Retinitis Pigmentosa Fighting Blindness (UK). Ambreen Kalhoro was the recipient of an Iris Fund Clinical Research Fellowship and Michel Michaelides is the recipient of an FFB Career Development Award.

Supplemental data

Supplemental data for this article can be accessed on the publisher’s website at http://dx.doi.org/10.1080/13816810.2017.1289544.

Additional information

Funding

This work was supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust and UCL Institute of Ophthalmology (UK), Fight for Sight including the Mercer Fund (UK), the Macular Society (UK), Moorfields Eye Hospital Special Trustees (UK), Moorfields Eye Charity (UK), the Foundation Fighting Blindness (FFB; USA), Retinitis Pigmentosa Fighting Blindness (UK). Ambreen Kalhoro was the recipient of an Iris Fund Clinical Research Fellowship and Michel Michaelides is the recipient of an FFB Career Development Award.