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.
Highlights
Conflict of interestAll authors declare no conflict of interest. S.R.F
Acromelic frontonasal dysostosis and ZSWIM6 mutation phenotypic spectrum and mosaicism Twigg, Stephen R F; Ousager, Lilian Bomme; Miller, Kerry A; Zhou, Yan; Elalaoui, Siham C; Sefiani, Abdelaziz; Bak, G
Acromelic frontonasal dysostosis (AFND) is an extremely rare frontonasal malformation (FNM) with fewer than 20 recognizable cases described in the literature
Summary
All authors declare no conflict of interest. S.R.F. Acromelic frontonasal dysotosis (AFND; MIM 603671) is characterized by a combination of characteristic frontonasal malformation (FNM) with limb defects and anomalies of the brain and usually occurs as a sporadic disorder. Possible vertical transmission [5] suggested a dominant mechanism, subsequently confirmed by identification of the underlying heterozygous mutation in four AFND cases [6]. These four cases were found to carry an identical mutation of ZSWIM6 (MIM: 615951; c.3487C>T; p.Arg1163Trp), all apparently de novo in origin. In a mildly affected parent we demonstrate mosaicism, confirming that this mechanism can result in a milder phenotype within the FNM spectrum
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