This variant is classified as a variant of unknown significance because its contribution to a syndrome consisting of dilated cardiomyopathy, septooptic dysplasia, hypogonadotropic hypogonadism, and dysmorphic features has not been confirmed.
Reinstein et al. (2015) studied a multiply consanguineous Bedouin family in which 2 brothers exhibited dilated cardiomyopathy, septooptic dysplasia, hypogonadotropic hypogonadism, and dysmorphic features. Chromosomal microarray in the older brother showed no copy number variants (CNVs), but multiple runs of homozygosity were detected. Whole-exome sequencing in the 2 affected sibs revealed homozygosity for a c.98T-C transition in the TAX1BP3 gene (c.98T-C, NM_014604.3), resulting in an ile33-to-thr (I33T) substitution at a highly conserved residue within the core of a hydrophobic binding pocket. The unaffected parents and 7 unaffected sibs were heterozygous for the mutation. Brain MRI in the affected brothers revealed agenesis of the corpus callosum and absence of the septum pellucidum in both; the older brother had a normal-sized sella with no evidence of pituitary adenoma or hypothalamic mass, whereas the younger brother had a thin pituitary gland. Funduscopy in the older sib revealed bilateral inferior segmental optic disc hypoplasia with an inferior double-ring sign, and optical coherence measurements showed thinning of the optic nerve fibers; no ophthalmologic features were reported for the younger brother. Both brothers were tall, with height above the 90th percentile. Dysmorphic features included macrocephaly, long face, midface hypoplasia, hypertelorism, downslanting palpebral fissures, broad nasal ridge and bridge, low-set posteriorly rotated and cupped ears, and dental anomalies, including dental crowding and single central incisor. Echocardiography showed severe dilated cardiomyopathy with prominent involvement of the right ventricle in both sibs. The younger brother died after cardiac transplantation at age 18 years; postmortem cardiac examination showed nonspecific ischemic cardiomyopathy, normal valves, normal coronary arteries, and multiple fibrotic scars in the left ventricle and septum.
