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

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 wi...

Full description

Saved in:

Bibliographic Details
Published in:	Clinical genetics Vol. 86; no. 4; pp. 318 - 325
Main Authors:	Lohan, S., Spielmann, M., Doelken, S.C., Flöttmann, R., Muhammad, F., Baig, S.M., Wajid, M., Hülsemann, W., Habenicht, R., Kjaer, K.W., Patil, S.J., Girisha, K.M., Abarca-Barriga, H.H., Mundlos, S., Klopocki, E.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-10-2014
Subjects:	Abnormalities, Multiple - genetics Abnormalities, Multiple - pathology Chromosomes, Human, Pair 7 - genetics CNVs Congenital diseases Ectromelia - genetics Ectromelia - pathology Female Fingers - abnormalities Fingers - pathology Foot Deformities, Congenital - genetics Foot Deformities, Congenital - pathology Gene Duplication Gene Expression Regulation Genetic disorders Genotype & phenotype Hand Deformities, Congenital - genetics Hand Deformities, Congenital - pathology Hedgehog Proteins - genetics Humans Laurin-Sandrow syndrome Male microduplication Nose - abnormalities Nose - pathology Pedigree Polydactyly - genetics Polydactyly - pathology Regulatory Sequences, Nucleic Acid - genetics SHH Syndactyly - genetics Syndactyly - pathology Toes - abnormalities Toes - pathology ZRS-associated syndromes Laurin-Sandrow syndrome SHH microduplication ZRS-associated syndromes CNVs
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ark:/67375/WNG-NJ17B06Z-T ArticleID:CGE12352 Deutsche Forschungsgemeinschaft Fig S1. Confirmation of microduplications on 7q36 by qPCR. An RQ 1.0 indicates normal copy number i.e. two copies. An RQ value of 1.5 displays three copies of an analyzed amplicon. The analyzed families are illustrated by different colored bars. For families 2 and 5 a breakpoint analysis could be made. Both families show microhomology at the breakpoints on 7q36 marked by boxes [family 2 three nucleotides (GTA), family 5 two nucleotides (CA)]. Telomeric and centromeric reference sequences are indicated on top (tel. ref. seq. and cen. ref. seq.).Table S1. Quantitative real-time polymerase chain reaction (qPCR) primers (a) and sequencing primers for breakpoint detection in families 2 and 5 (b). Berlin-Brandenburg School for Regenerative Therapies (BSRT) istex:AB5A41265321F45DE9B655F9641D5C6C6EF42D4F ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0009-9163 1399-0004
DOI:	10.1111/cge.12352