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Targeted clinical exome sequencing led to the identification of a homozygous missense variant in <jats:italic>OTX2<\/jats:italic>. Since only dominant mutations within <jats:italic>OTX2<\/jats:italic> have been associated with cases of syndromic microphthalmia, retinal dystrophy with or without pituitary dysfunctions, this represents the first report of an <jats:italic>OTX2<\/jats:italic> recessive mutation. Part of the phenotype, including ataxia, myopathy and multiple mitochondrial respiratory chain defects, seemed not related to <jats:italic>OTX2<\/jats:italic>. Further analysis of next generation sequencing (NGS) data revealed additional candidate variants: a homozygous variant in <jats:italic>LETM1<\/jats:italic>, and heterozygous rare variants in <jats:italic>AFG3L2<\/jats:italic> and <jats:italic>POLG<\/jats:italic>. All three genes encode mitochondrial proteins and the last two are known to be associated with ataxia, a neurological sign present also in the father of the proband. With our study, we aim to encourage the integration of NGS data with a detailed analysis of clinical description and family history in order to unravel composite genotypes sometimes associated with complicated phenotypes.<\/jats:p>","DOI":"10.1002\/ajmg.a.61092","type":"journal-article","created":{"date-parts":[[2019,2,18]],"date-time":"2019-02-18T05:34:58Z","timestamp":1550468098000},"page":"827-831","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Homozygous variant in <i>OTX2<\/i> and possible genetic modifiers identified in a patient with combined pituitary hormone deficiency, ocular involvement, myopathy, ataxia, and mitochondrial impairment"],"prefix":"10.1002","volume":"179","author":[{"given":"Alessia","family":"Catania","sequence":"first","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan 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