You-Hoover-Fong Syndrome

A number sign (#) is used with this entry because of evidence that You-Hoover-Fong syndrome (YHFS) is caused by compound heterozygous mutation in the TELO2 gene (611140) on chromosome 16p13.

Clinical Features

You et al. (2016) reported 6 patients, including 3 sibs and 3 unrelated patients, with a similar phenotype characterized by severely delayed global development, microcephaly, abnormal balance, and a movement disorder. All 3 sibs had poor feeding and hypotonia in early infancy. As teenagers, they were not ambulant and had impaired balance and a movement disorder, often with mild spasticity but without chorea. All 3 sibs also had hearing loss, cortical visual impairment, poor or absent speech, brachydactyly and clinodactyly, 4/5 toe syndactyly, and congenital heart disease comprising developmental abnormalities of the great vessels; 2 sibs had oral frenuli/ankyloglossia. Common dysmorphic features in this family included blue sclerae, joint laxity, and pectus carinatum. The 3 unrelated patients had a similar disorder, with severely delayed global development, intellectual disability with absent speech, microcephaly, and lack of or poor ambulation due to a movement disorder, which was described as ataxia in 1 patient; all had poor balance. More variable features, only noted in some patients and not common among the sibs, included cleft palate, kyphoscoliosis, abnormal sleep pattern, and rotary nystagmus. Only 1 patient had overt seizures. Brain imaging of 3 patients from different families was normal.

Inheritance

The transmission pattern of You-Hoover-Fong syndrome in the families reported by You et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 patients from 4 unrelated families with You-Hoover-Fong syndrome, You et al. (2016) identified compound heterozygous mutations in the TELO2 gene (611140.0001-611140.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient cells showed normal TELO2 mRNA levels, but decreased amounts of mutant protein, suggesting that it is unstable. Patient cells also showed decreased levels of TTI1 (614425) and TTI2 (614426), consistent with destabilization of the TTT complex. Patient cells showed no significant changes in levels of PIKK proteins, no abnormalities in DNA repair, and no changes in telomere length compared to controls. However, inhibition of HSP90 (see 140571) resulted in further reduction of the TTT complex and negative effect on the abundance of certain PIKKS, including ATM (607585) and PRKDC (600899). You et al. (2016) suggested that stress conditions leading to disrupted function of the TTT complex may occur in certain cells at critical times in development, resulting in the phenotypic features observed in the patients.