Microcephaly

Gene: AFF3

Green List (high evidence)

16 affected individuals reported with de novo missense variants. All variants occurred within the degron motif of the ALF domain. The highly conserved 9-amino acid motif mediates the interaction with SIAH E3 ubiquitin ligases and regulates their degradation. Thirteen of the probands carried variants affecting the same codon in exon 6, ala258.

All probands presented with severe developmental epileptic encephalopathy along with mesomelic dysplasia (12/18) and failure to thrive (14/18). The skeletal features included short forearms, radial head dislocation/subluxation, triangular and/or short tibia, fibular hypoplasia, hip dislocation, and tarsal and/or metatarsal synostosis resembling Nievergelt/Savarirayan mesomelic skeletal dysplasia. Other features included microcephaly (9/18), global brain atrophy and/or ventriculomegaly (13/15), fibular hypoplasia (12/16), horseshoe or hypoplastic kidney (13/17), abnormalities of muscle tone (12/16), gastroesophageal reflux disease (6/16), and other gastrointestinal symptoms (14/17). The patients also shared common dysmorphic facial features such as a bulbous nasal tip (10/15), a wide mouth (10/16) often with a square upper lip, abnormalities of the teeth and gums (12/15), and hypertrichosis (12/15). The constellation of features recalled some features of CHOPS syndrome, which is caused by mutations in a related gene, AFF4.
Sources: Literature

Created: 12 May 2021, 9:28 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
KINSSHIP syndrome, MIM# 619297

Publications

• 31388108
• 33961779