Homozygous variant in OTX2 and possible genetic modifiers identified in a patient with combined pituitary hormone deficiency, ocular involvement, myopathy, ataxia, and mitochondrial impairment

Abstract

Here we report on a singleton patient affected by a complicated congenital syndrome characterized by growth delay, retinal dystrophy, sensorineural deafness, myopathy, ataxia, combined pituitary hormone deficiency, associated with mitochondrial impairment. Targeted clinical exome sequencing led to the identification of a homozygous missense variant in OTX2. Since only dominant mutations within OTX2 have been associated with cases of syndromic microphthalmia, retinal dystrophy with or without pituitary dysfunctions, this represents the first report of an OTX2 recessive mutation. Part of the phenotype, including ataxia, myopathy and multiple mitochondrial respiratory chain defects, seemed not related to OTX2. Further analysis of next generation sequencing (NGS) data revealed additional candidate variants: a homozygous variant in LETM1, and heterozygous rare variants in AFG3L2 and POLG. 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. K E Y W O R D S AFG3L2, complex congenital syndrome, LETM1, OTX2, POLG 1 | INTRODUCTION In the last decade, the development of new next generation sequencing (NGS) technologies such as whole genome/exome sequencing, has rapidly offered a growing opportunity to provide large-scale and high sensitivity genomic screening allowing the identification of new pathogenic variants associated with rare inherited diseases and overcoming most of the limitations of a candidate-gene based approach to diagnostics. Even though, complex congenital phenotypes in singleton cases, thus without a clear Mendelian inheritance pattern, still represent one of the main pitfalls of these techniques. A close interaction between clinicians and geneticists is fundamental in order to allow a proper evaluation of the NGS data, especially considering the growing number of reports about cases with intricate clinical presentation and composite genetic basis.In this report, we describe a singleton patient affected by a complicated congenital syndrome characterized by growth delay, retinal dystrophy, sensorineural deafness, myopathy, ataxia, combined pituitary hormone deficiency (CPHD), associated with mitochondrial impairment. Genetic and clinical data were deeply investigated in order to find genotype-phenotype correlations. | MATERIALS AND METHODSClinical, genetic, and histo/biochemical evaluations were performed upon acquisition of informed consent from all the subjects involved in this study, as required by the Ethical Committee of the Fondazione † Alessia Catania and Andrea Legati contributed equally to this study.

Multifaceted Roles of AFG3L2, a Mitochondrial ATPase in Relation to Neurological Disorders

“…Hence, a keen investigation with family history, physical examinations, genetic testing, and neuroimaging might be useful in diagnosing this disease. Very recently, c.2167G > A; V723M variant is designated as a likely pathogenic variant of AFG3L2 that is related to myopathy, respiratory chain complex defects, and ataxia [ 122 ] in a single patient who is also affected by congenital pituitary hormone deficiency and deafness due to involvement of other mutated genes as well.…”

Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes

“…Heterozygous mutations of OTX2 cause severe ocular malformations, which range from bilateral anophthalmia to retinal defects resembling LCA and pigmentary retinopathy [180]. OTX2 loss-of-function mutations are frequently associated with coloboma, optic nerve hypoplasia or aplasia, microcephaly, brain, and pituitary anomalies and combined pituitary hormone deficiency [181][182][183]. Heterozygous mutations in OTX2 associated with early-onset retinal dystrophy with atypical maculopathy and bilateral microphthalmos have been reported [184].…”