A number sign (#) is used with this entry because of evidence that retinal dystrophy and obesity (RDOB) is caused by homozygous mutation in the TUB gene (601197) on chromosome 11p15. One such family has been reported.

Borman et al. (2014) studied a consanguineous Caucasian family from the United Kingdom in which 3 sibs had retinal dystrophy and obesity. The proband was an 18-year-old male who presented at age 11 with a 2-year history of deteriorating vision, at which time he had no perception of light in the left eye and decreased visual acuity (20/40) in the right eye. Examination revealed a bilateral myopic and astigmatic refractive error, with a 'blonde' fundus on the right and total retinal detachment with vitreous hemorrhage on the left. At 18 years of age, visual acuity was measured at 20/30 on the right with no light perception on the left, and bilateral myopic and astigmatic refractive errors were confirmed. Color vision testing showed a general disturbance involving protan, deutan, and tritan axes. Funduscopy of the left eye showed total retinal detachment, whereas the right eye showed widespread retinal pigment epithelial (RPE) atrophy, generalized retinal pallor, arteriolar attenuation, fine peripheral pigmentary mottling, and white dots throughout the retina, with sparing of the macula. Perimetry testing showed that the right visual field was reduced to the central 15 degrees. Electroretinography was nonrecordable on the left, and on the right showed absent rod responses and a small residual cone response, consistent with a severe generalized rod-cone dystrophy. Retinal ocular coherence tomography (OCT) showed preservation of the photoreceptor inner segment/outer segment (IS/OS) junction at the fovea, with loss of this layer in the parafoveal region corresponding to the fundus autofluorescence (FAF) image, which demonstrated an annulus of hyperautofluorescence. The patient was obese, with a body mass index (BMI) of 30, but exhibited no additional clinical features suggestive of Bardet-Biedl syndrome (see 209900) or Alstrom syndrome (203800). An older brother and younger sister also had reduced visual acuity and myopic astigmatic refractive errors. The 21-year-old brother was unaware of any ocular problems, but funduscopy showed bilateral retinal pallor with symmetric widespread RPE atrophy, arteriolar attenuation, fine peripheral pigmentary mottling, and retinal white dots with macular sparing; there was hypofluorescent mottling along the vascular arcades but normal foveal autofluorescence signal, and OCT showed preservation of the IS/OS layer at the fovea, with outer retinal debris at the RPE in the parafoveal region. The 9-year-old sister was also asymptomatic but had widespread RPE atrophy and inferior retinal pigmentary mottling; OCT and FAF imaging were normal. The older brother had a BMI in the normal range, whereas the younger sister was classified as obese, falling into the 98th percentile for age and gender. Their parents and 2 older sisters had no ocular symptoms and normal fundi on examination; the father was obese with a BMI of 30.

By whole-exome sequencing in an 18-year-old male with retinal dystrophy and obesity, who was born of consanguineous parents and was negative for mutation in known retinal disease-associated genes, Borman et al. (2014) identified homozygosity for a 2-bp deletion in the TUB gene (601197.0001). Sanger sequencing confirmed the mutation and demonstrated that the proband's 2 affected sibs were also homozygous for the deletion, whereas the unaffected parents and an unaffected sib were heterozygous carriers. The mutation was not found in more than 6,000 exomes in the NHLBI Exome Variant Server database. Screening of the TUB gene in 96 additional probands with childhood-onset autosomal recessive retinitis pigmentosa and in 55 patients with severe obesity and a variety of ocular phenotypes yielded no additional pathogenic variants.