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An ophthalmological assessment in all families was followed by targeted <jats:italic>MFRP<\/jats:italic> and <jats:italic>PRSS56<\/jats:italic> testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct <jats:italic>MFRP<\/jats:italic> mutations were found in 10\/21 families (47.6%), five of which are novel including a deletion spanning the 5\u2032 untranslated region and the first coding part of exon 1. Most cases harbored homozygous mutations (8\/10), while a compound heterozygous and a monoallelic genotype were identified in the remaining ones (2\/10). Six distinct <jats:italic>PRSS56<\/jats:italic> 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 <jats:italic>MFRP<\/jats:italic> 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 first <jats:italic>MFRP<\/jats:italic> genomic rearrangement, offering opportunities for gene-based therapies in <jats:italic>MFRP<\/jats:italic>-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the <jats:italic>MFRP<\/jats:italic> and <jats:italic>PRSS56<\/jats:italic> genes in MCOP and NNO.<\/jats:p>","DOI":"10.1038\/s41598-019-57338-2","type":"journal-article","created":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T11:03:18Z","timestamp":1580209398000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0266-4500","authenticated-orcid":false,"given":"Basamat","family":"Almoallem","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Arno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"De Zaeytijd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Verdin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Balikova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingele","family":"Casteels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomy","family":"de Ravel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Hull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Suzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Destr\u00e9e","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Ainsworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R.","family":"Webster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart P.","family":"Leroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony T.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5609-6895","authenticated-orcid":false,"given":"Elfride","family":"De Baere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,28]]},"reference":[{"key":"57338_CR1","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1136\/jmg.30.8.664","volume":"30","author":"M Warburg","year":"1993","unstructured":"Warburg, M. 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