Alazami-Yuan Syndrome

A number sign (#) is used with this entry because of evidence that Alazami-Yuan syndrome (ALYUS) is caused by homozygous mutation in the TAF6 gene (602955) on chromosome 7q22.

Clinical Features

Alazami et al. (2015) reported an 11-year-old boy, born of consanguineous Saudi Arabian parents, with intellectual disability and dysmorphic features. He had hypotonia and poor feeding soon after birth, and later showed delayed psychomotor development with poor speech acquisition. Dysmorphic features included strabismus, low hairline, synophrys, curved eyebrows, prominent nasal bridge, short columella, hypoplastic nasal wings, and high-arched palate with crowded teeth. He also had widely spaced nipples and cryptorchidism. Brain imaging was normal.

Yuan et al. (2015) reported a 4-year-old boy, born of consanguineous Turkish parents, with ALYUS. He had delayed psychomotor development with intellectual disability. Physical features included short stature, microcephaly, narrow shoulders, single transverse palmar crease on the right hand, unilateral cryptorchidism, hirsutism, and a dysmorphic facial appearance, including arched eyebrows with synophrys, long curly eyelashes, long philtrum, prominent nose, microstomia, and thin upper lip. These features were reminiscent of Cornelia de Lange syndrome (see, e.g., CDLS1, 122470). Family history revealed 2 deceased infant sibs with similar features. Yuan et al. (2015) also independently reported 3 sibs from the consanguineous Saudi family reported by Alazami et al. (2015) who had a similar disorder with milder dysmorphic facial features.

Inheritance

The transmission pattern of ALYUS in the families reported by Yuan et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In an 11-year-old boy with intellectual disability and dysmorphic features, Alazami et al. (2015) identified a homozygous missense mutation in the TAF6 gene (I71T; 602955.0001). The family was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed.

In a Turkish boy, born of consanguineous parents, with ALYUS, Yuan et al. (2015) identified a homozygous missense mutation in the TAF6 gene (R46C; 602955.0002). The patient was part of a cohort of 32 Turkish patients with a clinical diagnosis of CDLS who underwent genome sequencing. In addition, 3 sibs from the consanguineous Saudi family with a similar disorder identified by Alazami et al. (2015) were found to be homozygous for the I71T mutation. The mutations segregated with the disorder in both families. In vitro functional expression studies in a Drosophila cell line showed that both mutations reduced the binding interaction with other components of the transcription factor IID complex (TFIID; see 313650), with the I71T variant showing a more deleterious effect than R45C. Transfection of the mutations into yeast resulted in a slight, but not obvious, growth reduction. The findings were consistent with a loss of function and suggested that the phenotype resulted from changes in transcriptional regulation pathways.