An atypical 0.73 MB microduplication of 22q11.21 and a novel SALL4 missense mutation associated with thumb agenesis and radioulnar synostosis

Abstract

We describe a 0.73 Mb duplication of chromosome 22q11.21 between LCR-B and LCR-D and a missense mutation in a conserved C2H2 zinc finger domain of SALL4 in a cognitively normal patient with multiple skeletal anomalies including radioulnar synostosis, thumb aplasia, butterfly vertebrae, rib abnormalities, and hypoplasia of the humeral and femoral epiphyses. 22q11.21 is a common site for microdeletions and their reciprocal microduplications as a result of non-allelic homologous recombination between its multiple low copy repeat regions (LCR). DiGeorge /Velocardiofacial syndrome (DG/VCFS) is classically caused by a 3 Mb deletion between LCR-A and LCR-D or a 1.5 Mb deletion between LCR-A and LCR-B. The reciprocal syndrome to DG/VCFS is the recently described 22q11.2 microduplication, which usually presents with the typical 3 Mb or 1.5 Mb duplication. Numerous atypical deletions and duplications have been reported between other LCRs. Typically, SALL4-related Duane-radial ray syndrome is caused by deletions or nonsense mutations; the only missense SALL4 mutation described prior was thought to result in gain of function and produced cranial midline defects. The skeletal anomalies presented in this report have not been previously described in association with 22q11.2 microduplication nor SALL4 mutations.

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

“…Currently, there is no evidence to suggest that the 19p13.3 duplication is clinically significant and that the involved genes are triplosensitive; furthermore, this patient did not have a significantly more severe phenotype than his younger sister (patient 2), who did not have the 19p13.3 duplication. In another case, a patient is described with a central 22q11.2 duplication already recognized to have more than one genetic aberration (Diehl et al., ). This 3‐year‐old female patient had an additional missense mutation in the SALL4 gene and presented with normal cognition and multiple skeletal anomalies, including left radioulnar synostosis, thumb aplasia, rib abnormalities, hypoplasia of the humeral and femoral epiphyses, and butterfly vertebrae.…”

“…Our study reinforces the notion that atypical nested 22q11.2 duplications are associated with a broad phenotypic spectrum, Only symptomatic individuals are included in this table. Central duplications cases included those between LCR22B and LCR22D described in this study, published in the literature (Diehl et al, 2015;Fan et al, 2007;Fernandez et al, 2009;Ou et al, 2008;Pebrel-Richard et al, 2012;Tucker et al, 2014) and within the DECIPHER database with clinical information and one CNV (https://decipher.sanger.ac.uk). Typical proximal duplication cases included those 3 Mb in size between LCR22A and LCR22D (Wenger et al, 2016).…”

“…To date, many individuals have been described with atypical nested 22q11.2 deletions between LCR22B and LCR22D (Clements et al., ; Rump et al., ; Wentzel et al., ). In contrast, very few cases with atypical nested 22q11.2 duplications have been reported (Clements et al., ; Diehl, Mu, Batista, & Gunay‐Aygun, ; Fan et al., ; Fernandez et al., ; Pebrel‐Richard et al., ; Tucker et al., , ). Here, we describe 13 individuals from six families with atypical nested 22q11.2 duplications between LCR22B and LCR22D.…”

SALL4, the missing link between stem cells, development and cancer

“…These are nonsense mutations, short duplications, or deletions. Two cases of missense SALL4 mutations around the coding region for the ZF4 cluster were also reported 6162 .…”

22q11.2 microduplication syndrome with associated esophageal atresia/tracheo‐esophageal fistula and vascular ring

“…Once a 22q11.2 microduplication is confirmed, it is important to search for other mutations, as it is likely that other genes may play a role in the phenotypic expression. For example, more recent reports are describing concomitant chromosomal imbalances along with the 22q11.2 microduplication, such as coexisting deletions, additional duplications, missense mutations, and reciprocal translocations .…”