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The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56

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Abstract
This study aimed to genetically and clinically characterize a unique cohort of 25 individuals from 21 unrelated families with autosomal recessive nanophthalmos (NNO) and posterior microphthalmia (MCOP) from diferent ethnicities. An ophthalmological assessment in all families was followed by targeted MFRP and PRSS56 testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct MFRP mutations were found in 10/21 families (47.6%), fve of which are novel including a deletion spanning the 5′ untranslated region and the frst coding part of exon 1. Most cases harbored homozygous mutations (8/10), while a compound heterozygous and a monoallelic genotype were identifed in the remaining ones (2/10). Six distinct PRSS56 mutations were found in 9/21 (42.9%) families, three of which are novel. Similarly, homozygous mutations were found in all but one, leaving 2/21 families (9.5%) without a molecular diagnosis. Clinically, all patients had reduced visual acuity, hyperopia, short axial length and crowded optic discs. Retinitis pigmentosa was observed in 5/10 (50%) of the MFRP group, papillomacular folds in 12/19 (63.2%) of MCOP and in 3/6 (50%) of NNO cases. A considerable phenotypic variability was observed, with no clear genotype-phenotype correlations. Overall, our study represents the largest NNO and MCOP cohort reported to date and provides a genetic diagnosis in 19/21 families (90.5%), including the frst MFRP genomic rearrangement, ofering opportunities for gene-based therapies in MFRP-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the MFRP and PRSS56 genes in MCOP and NNO.
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Multidisciplinary

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MLA
Almoallem Mohammed, Basamat, et al. “The Majority of Autosomal Recessive Nanophthalmos and Posterior Microphthalmia Can Be Attributed to Biallelic Sequence and Structural Variants in MFRP and PRSS56.” SCIENTIFIC REPORTS, vol. 10, 2020, doi:10.1038/s41598-019-57338-2.
APA
Almoallem Mohammed, B., Arno, G., De Zaeytijd, J., Verdin, H., Balikova, I., Casteels, I., … De Baere, E. (2020). The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56. SCIENTIFIC REPORTS, 10. https://doi.org/10.1038/s41598-019-57338-2
Chicago author-date
Almoallem Mohammed, Basamat, Gavin Arno, Julie De Zaeytijd, Hannah Verdin, Irina Balikova, Ingele Casteels, Thomy de Ravel, et al. 2020. “The Majority of Autosomal Recessive Nanophthalmos and Posterior Microphthalmia Can Be Attributed to Biallelic Sequence and Structural Variants in MFRP and PRSS56.” SCIENTIFIC REPORTS 10. https://doi.org/10.1038/s41598-019-57338-2.
Chicago author-date (all authors)
Almoallem Mohammed, Basamat, Gavin Arno, Julie De Zaeytijd, Hannah Verdin, Irina Balikova, Ingele Casteels, Thomy de Ravel, Sarah Hull, Martina Suzani, Anne Destrée, Michelle Peng, Denise Williams, John R. Ainsworth, Andrew R. Webster, Bart Leroy, Anthony T. Moore, and Elfride De Baere. 2020. “The Majority of Autosomal Recessive Nanophthalmos and Posterior Microphthalmia Can Be Attributed to Biallelic Sequence and Structural Variants in MFRP and PRSS56.” SCIENTIFIC REPORTS 10. doi:10.1038/s41598-019-57338-2.
Vancouver
1.
Almoallem Mohammed B, Arno G, De Zaeytijd J, Verdin H, Balikova I, Casteels I, et al. The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56. SCIENTIFIC REPORTS. 2020;10.
IEEE
[1]
B. Almoallem Mohammed et al., “The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56,” SCIENTIFIC REPORTS, vol. 10, 2020.
@article{8655944,
  abstract     = {This study aimed to genetically and clinically characterize a unique cohort of 25 individuals from 21 unrelated families with autosomal recessive nanophthalmos (NNO) and posterior microphthalmia (MCOP) from diferent ethnicities. An ophthalmological assessment in all families was followed by targeted MFRP and PRSS56 testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct MFRP mutations were found in 10/21 families (47.6%), fve of which are novel including a deletion spanning the 5′ untranslated region and the frst coding part of exon 1. Most cases harbored homozygous mutations (8/10), while a compound heterozygous and a monoallelic genotype were identifed in the remaining ones (2/10).
Six distinct PRSS56 mutations were found in 9/21 (42.9%) families, three of which are novel. Similarly, homozygous mutations were found in all but one, leaving 2/21 families (9.5%) without a molecular diagnosis. Clinically, all patients had reduced visual acuity, hyperopia, short axial length and crowded optic discs. Retinitis pigmentosa was observed in 5/10 (50%) of the MFRP group, papillomacular folds in 12/19 (63.2%) of MCOP and in 3/6 (50%) of NNO cases. A considerable phenotypic variability was observed, with no clear genotype-phenotype correlations. Overall, our study represents the largest NNO and MCOP cohort reported to date and provides a genetic diagnosis in 19/21 families (90.5%), including the frst MFRP genomic rearrangement, ofering opportunities for gene-based therapies in MFRP-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the MFRP and PRSS56 genes in MCOP and NNO.},
  articleno    = {1289},
  author       = {Almoallem Mohammed, Basamat and Arno, Gavin and De Zaeytijd, Julie and Verdin, Hannah and Balikova, Irina and Casteels, Ingele and de Ravel, Thomy and Hull, Sarah and Suzani, Martina and Destrée, Anne and Peng, Michelle and Williams, Denise and Ainsworth, John R. and Webster, Andrew R. and Leroy, Bart and Moore, Anthony T. and De Baere, Elfride},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keywords     = {Multidisciplinary},
  language     = {eng},
  pages        = {10},
  title        = {The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56},
  url          = {http://dx.doi.org/10.1038/s41598-019-57338-2},
  volume       = {10},
  year         = {2020},
}

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