Limb disordersGene: LMBR1
Variants within LMBR1 coding sequence:
PMID:11090342 - Ianakiev et al - 2001- found a genomic 4- to 6-kb deletion in LMBR1 in 5 unrelated Brazilian families with acheiropody. The deletion led to a trascript lacking exon 4 and introducing a premature stop codon downstream of exon 3. Haplotype analysis confirmed the expectation that a single common ancestral mutation was the cause of all the cases.
PMID: 26749485 - Shamseldin et al 2016 - patient with acheiropodia who had a nullizygous deletion of 102 kb spanning LMBR1.
The ZRS (zone of polarizing activity regulatory sequence) is a sonic hedgehog (SHH) regulatory region of approx 800bp. It is not thought to affect the expression LMBR1.
Variants and duplications affecting the ZRS within intron 5 of the LMBR1 gene:
Numerous reports of heterozygous variants in ZRS being associated with preaxial polydactyly/Werner mesomelic syndrome - (PMID: 31395945 - Xu et al 2019 - 1 case, 446T>A ZRS), (PMID: 19847792 Wieczorek et al. (2010) - 2 cases with variants 404G>A and 404G>C ZRS), (PMID: 24965254 Norbnop et al. (2014) - 2 cases, one familial and one sporadic with 406A>G and 404G>A ZRS variants), (PMID: 24777739 - VanderMeer et al. (2014) - 1 case - 5 generation family with a c.402C->T variant (A more severely affected daughter was homozygous for the same mutation)). Other cases listed in OMIM.
PMID: 28127823 - Xiang et al 2017 - report 6/102 of patients with preaxial polydactyly type I with variants in a region upstream of the ZRS.
Reports of duplications covering parts of the ZRS also being associated with a limb phenotype.
PMID: 19847792 - Wieczorek et al. (2010) - report 2 families (families 3 and 4) with duplications (73-kb and 276-kb) affecting the ZRS region. Members of family 3 had Haas type polysyndactyly and family 4 had triphalangeal thumb-polysyndactyly syndrome.
PMID: 18178630 - Klopocki et al 2008 - report a large 4-generation pedigree with variable triphalangeal thumb and polysyndactyly, No point mutations found in the LMBR1 gene but array CGH analysis identified a heterozygous 589-kb duplication comprising the ZRS.
PMID: 18417549 - Sun et al 2009 - in 6 Han Chinese families with Triphalangeal thumb-polysyndactyly syndrome they identified duplications of ZRS which segregated with the limb phenotypes in all families.
PMID: 19291772 - Wu et al 2009 - in a Chinese family with type IV syndactyly and tibial hypoplasia they detected a duplication of between 105 to 115 kb.
PMID: 24456159 - Lohan et al 2104 - report on 5 unrelated families with overlapping microduplications encompassing the ZPA regulatory sequence. Larger duplications of the ZRS region (>80 kb) are associated with Haas-type polysyndactyly, whereas smaller duplications (<80 kb) result in a Laurin-Sandrow syndrome phenotype.
Summary: > 3 cases where SNVs in the ZRS are found in patients with polydactyly. In >3 cases duplications covering parts of the ZRS were found in patients with a limb phenotype. Currently variants in the ZRS would NOT be reported via WGS. Duplications > 10Kb covering the LMBR1 gene would be picked up as the gene is green.
Created: 26 Nov 2019, 12:43 p.m. | Last Modified: 26 Nov 2019, 4:10 p.m.
Panel Version: 1.127
Comment when marking as ready: Laurin-Sandrow syndrome represents radial aplasia but with ulnar dimelia, therefore phenotype appropriate for inclusion. Note that reported cases with this phenotype have resulted from microduplications. Spectrum of other radial ray manifestations associated with variants in this gene. Therefore included.
Created: 11 May 2017, 10:24 a.m.
Comment on mode of inheritance: Laurin-Sandrow syndrome as the relevant phenotype for this panel
Created: 11 May 2017, 10:20 a.m.
Laurin-Sandrow syndrome (LSS) is caused by heterozygous mutation in an SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene.
Created: 18 Oct 2016, 1:26 p.m.
Comment when marking as ready: Numerous variants reported in these phenotypes
Created: 12 Jul 2016, 9:47 a.m.
Created: 17 Jun 2016, 8:05 a.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Acheiropody 200500; Hypoplastic or aplastic tibia with polydactyly 188740; Laurin-Sandrow syndrome 135750; Polydactyly, preaxial type II 174500; Syndactyly, type IV 186200; Triphalangeal thumb, type I 174500; Triphalangeal thumb-polysyndactyly syndrome 174500
Variants in this GENE are reported as part of current diagnostic practice
Ana Beleza: Tier 2
Mode of inheritance for gene LMBR1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Added phenotypes Triphalangeal Thumb-Polysyndactyly Syndrome; Laurin-Sandrow syndrome,135750; Triphalangeal thumb type I,174500 for gene: LMBR1
Victorian Clinical Genetics Services was added to LMBR1. Panel: Limb disorders Phenotypes for gene LMBR1 were set to Acheiropody 200500, Hypoplastic or aplastic tibia with polydactyly 188740, Laurin-Sandrow syndrome 135750, Polydactyly, preaxial type II 174500, Syndactyly, type IV 186200, Triphalangeal thumb, type I 174500, Triphalangeal thumb-polysyndactyly syndrome 174500, Polydactyly
Expert Review Green was added to LMBR1. Panel: Limb disorders UKGTN was added to LMBR1. Panel: Limb disorders Radboud University Medical Center, Nijmegen was added to LMBR1. Panel: Limb disorders Illumina TruGenome Clinical Sequencing Services was added to LMBR1. Panel: Limb disorders Expert list was added to LMBR1. Panel: Limb disorders Emory Genetics Laboratory was added to LMBR1. Panel: Limb disorders Model of inheritance for gene LMBR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
London South East RGC GSTT was added to LMBR1. Panel: Limb disorders
LMBR1 was added to Limb disorders panel. Sources: Viapath
LMBR1 was created by Ellen McDonagh