Acromelic frontonasal dysostosis and ZSWIM6 mutation: phenotypic spectrum and mosaicism

Abstract

Acromelic frontonasal dysostosis (AFND) is a distinctive and rare frontonasal malformation that presents in combination with brain and limb abnormalities. A single recurrent heterozygous missense substitution in ZSWIM6, encoding a protein of unknown function, was previously shown to underlie this disorder in four unrelated cases. Here we describe four additional individuals from three families, comprising two sporadic subjects (one of whom had no limb malformation) and a mildly affected female with a severely affected son. In the latter family we demonstrate parental mosaicism through deep sequencing of DNA isolated from a variety of tissues, which each contain different levels of mutation. This has important implications for genetic counselling.

Keywords: ZSWIM6; frontonasal malformation; mosaicism; preaxial polydactyly.

Figure 1

Clinical features of individuals with ZSWIM6 c.3487C>T mutations. (a) Subject 1‐1 showing facial features at about 1 year of age. Note hypertelorism and bifid nasal tip. (b,c) Neonatal appearance of Subject 1‐2, with severe FNM, hypertelorism, carp‐shaped mouth with notch in upper lip (b), and bifid great toes and clubfoot (c). (d) Brain magnetic resonance imaging of Subject 2 showing interhemispheric lipoma (white arrow), and severe hypertelorism. (e,f) Ultrasound images of Subject 3 showing orbital hypertelorism (e, arrows indicate the eyes) and hypoplastic nose (f, arrowhead). (g) Clinical appearance of Subject 3 with FNM, hypertelorism and clubfoot. Polydactyly is absent.

Figure 2

ZSWIM6 sequence analysis. (a) Sequence chromatograms showing ZSWIM6 c.3487C>T in Subjects 1‐2, 2 and 3 (red arrows). The C>T variant is absent in Subject 1‐1 (DNA from peripheral blood) and the parents of Subjects 2 and 3. (b) Deep sequence analysis for ZSWIM6 c.3487C>T. The left hand panel shows the percentage of the variant T allele detected in Subject 1‐1 and 1‐2. The value for Subject 1‐2 has been corrected to 50% and all other figures adjusted accordingly. The T allele is shown in red and the C allele in blue. The right hand panel shows the uncorrected read depths achieved for each sample.