Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are associated with Haas‐type polysyndactyly and Laurin‐Sandrow syndrome

Abstract

Laurin-Sandrow syndrome (LSS) is a rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. The genetic basis of LSS is currently unknown. LSS shows phenotypic overlap with Haas-type polysyndactyly (HTS) regarding the digital phenotype. Here we report on five unrelated families with overlapping microduplications encompassing the Sonic hedgehog (SHH) limb enhancer ZPA regulatory sequence (ZRS) on chromosome 7q36. Clinically, the patients show polysyndactyly phenotypes and various types of lower limb malformations ranging from syndactyly to mirror image polydactyly with duplications of the fibulae. We show that larger duplications of the ZRS region (>80 kb) are associated with HTS, whereas smaller duplications (<80 kb) result in the LSS phenotype. On the basis of our data, the latter can be clearly distinguished from HTS by the presence of mirror image polysyndactyly of the feet with duplication of the fibula. Our results expand the clinical phenotype of the ZRS-associated syndromes and suggest that smaller duplications (<80 kb) are associated with a more severe phenotype. In addition, we show that these small microduplications within the ZRS region are the underlying genetic cause of Laurin-Sandrow syndrome.

Femoral facial syndrome associated with a de novo complex chromosome 2q37 rearrangement

“…Thus, duplication of the limb enhancer HACNS1 is a candidate contributor to the femoral hypoplasia phenotype of the patient reported here. Similar duplications of cis ‐regulatory elements such as the SHH limb enhancer element ZRS ( Zone of Regulatory Sequence ) have been shown to cause a variety of limb phenotypes ranging from triphalangeal thumb to cup shaped polysyndactyly [Spielmann and Klopocki, ; Lohan et al, ]. In conclusion and not withstanding the unknown pathomechanisms, to our knowledge, our report is the first to describe a genetic cause of FFS and may thus help elucidating the genetic determinants of femoral growth.…”

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

“…Disruption of TADs by genomic rearrangements may then cause pathological interactions by perturbing gene expression [Spielmann and Klopocki, 2013;Spielmann and Mundlos, 2013;Lupiáñez et al, 2015]. In patients with skeletal dysmorphology (in particular of the hands), changes in noncoding elements have frequently been revealed by screening for CNVs [Klopocki et al, 2008Benko et al, 2009;Dathe et al, 2009;Gordon et al, 2009Gordon et al, , 2014Kurth et al, 2009;Spielmann et al, 2012;Lohan et al, 2014;Tayebi et al, 2014]. This genomic mechanism is not necessarily limited to these disorders.…”

Intrafamilial variability of ZRS‐associated syndrome: characterization of a mosaic ZRS mutation by pyrosequencing

“…The anteroposterior patterning of the digits requires signalling from the zone of polarizing activity (ZPA), a group of mesenchymal cells localized at the posterior margin of the tetrapod limb bud. ZRS gain-of-function anomalies are responsible for limb malformations (the so-called ZRS-associated syndromes) (4), with phenotypic presentation ranging through preaxial polydactyly and/or triphalangeal thumbs [PPD2 (MIM 174500)] [reviewed in (5) (4,(10)(11)(12), PPD2 with radial deficiency (13) and some cases of Laurin-Sandrow syndrome (LSS [MIM 135750]) (14). A highly conserved cis-regulatory enhancer called the ZPA regulatory sequence [ZRS (MIM 605522)] lies within intron 5 of the LMBR1 gene on chromosome 7q36, which is located 1 megabase upstream of its target gene, SHH in human (2,3).…”