Novel Mutation in the First Tunisian Family With Warburg Micro Syndrome.

Background And Purpose: Warburg Micro syndrome (WARBM) is a rare autosomal recessive genetic disease characterized by ocular, neurologic, and endocrine anomalies. WARBM is a phenotypically and genetically heterogeneous syndrome caused by mutations in , , , and . Here we present the clinical and genetic characterization of a consanguineous Tunisian family with a WARBM phenotype presenting two pathogenic variations, one of which is on .

Methods: We applied whole-exome sequencing (WES) to two affected young males presenting a WARBM-compatible phenotype.

Results: We reveal a new variation in (NM_012233.3: c.297del, p.Gln99fs) and another variation in (NM_000033: c.896A>G, p.His299Arg). Each of these mutations, which in silico predictions concluded as being pathogenic variations, affects a critical protein region. Both affected males presented a WARBM-compatible phenotype, with severe intellectual disability, severe developmental delay, postnatal growth delay, postnatal microcephaly, congenital bilateral cataracts, general hypotonia, and a thin corpus callosum without a splenium. However, intrafamilial clinical heterogeneity was present, since only the oldest child had large ears, microphthalmia, foot deformities, and a genital anomaly, and only the youngest child had microcornea. Despite the mutation identified in , our patients did not have any X-linked symptoms of adrenoleukodystrophy disorder that are usually caused by mutations, which prompted our interest in clinical monitoring.

Conclusions: WES analysis of a consanguineous Tunisian family with WARBM revealed a novel variation in (NM_012233.3: c.297del, p.Gln99fs) that is most likely pathogenic and allowed us to confirm the diagnosis of WARBM.