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Limb disorders v9.6 CRIPT Ida Ertmanska changed review comment from: PMID: 37013901 Averdunk et al., 2023
Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants.
P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86
P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr)
Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly.

Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4).
2 individuals were from Saudi Arabia, one from Turkey, and one African American.
Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4).
None of the patients had cataracts.
Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS).
Sources: Literature; to: PMID: 37013901 Averdunk et al., 2023
Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants.
P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86
P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr)
Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, feet abnormalities, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly.

Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4).
2 individuals were from Saudi Arabia, one from Turkey, and one African American.
Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4), feet anomalies including pes planus, pes calcaneovalgus, and skewfoot |(4/4).
None of the patients had cataracts.
Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS).
Sources: Literature
Limb disorders v9.6 CRIPT Ida Ertmanska Classified gene: CRIPT as Amber List (moderate evidence)
Limb disorders v9.6 CRIPT Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with toe syndactyly being a consistent feature. In addition, one patient had a proximally placed thumb, and all 6 had feet abnormalities including pes planus, pes calcaneovalgus, and skewfoot. Hence, this gene can be promoted to Green at the next update.
Limb disorders v9.6 CRIPT Ida Ertmanska Gene: cript has been classified as Amber List (Moderate Evidence).
Limb disorders v9.5 CRIPT Ida Ertmanska gene: CRIPT was added
gene: CRIPT was added to Limb disorders. Sources: Literature
Q3_26_promote_green tags were added to gene: CRIPT.
Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRIPT were set to 24389050; 27250922; 36630262; 37013901
Phenotypes for gene: CRIPT were set to Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347
Review for gene: CRIPT was set to GREEN
Added comment: PMID: 37013901 Averdunk et al., 2023
Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants.
P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86
P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr)
Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly.

Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4).
2 individuals were from Saudi Arabia, one from Turkey, and one African American.
Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4).
None of the patients had cataracts.
Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS).
Sources: Literature
Limb disorders v7.29 GNAS Eleanor Williams commented on gene: GNAS: The mode of inheritance of this gene should ideally be set to both MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) AND MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) since the gene has both paternally and maternally imprinted transcripts. However, this is not currently possible in PanelApp.

With the current mode of inheritance of MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown variants in imprinted transcripts will only be tiered under the 'incomplete penetrance' mode.

We are currently looking at the best options for updating the mode of inheritance to cover the maternal and paternal imprinting seen in this gene.
Limb disorders v6.6 BTRC Eleanor Williams edited their review of gene: BTRC: Added comment: PMID: 35908152 - Qui et al 2022 - using trio clinical exome sequencing, a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3. The duplication co-segregated with SHFM phenotypes in the family. Transcription levels of BTRC mRNA in lymphocytes of the proband was significantly higher than in the healthy control.

PMID: 36928426 Cova et al 2023 - show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. By re-engineering a human SHFM3-associated duplication in mice they observed ectopic interactions between the Fgf8 apical ectodermal ridge (AER) enhancers and two other genes in the locus, Lbx1 and Btrc. The same ectopic interactions were present in fibroblasts from a SHFM3 affected individual with duplication. In mice with the duplication a limb malformation was not observed. They also report a case of SHFM3 malformation associated with an inversion encompassing the DPDC, POLL and FBXW4 genes which when re-engineered in mice results in increased expression of genes, Lbx1 and Btrc, in an Fgf8-like pattern in the apical ectodermal ridge. Mice with the inversion were observed to have a digit phenotype.

In conclusion, point mutations in BTRC in association with SHFM3 have not been reported. It appears that changed expression of gene BTRC is related to the phenotype, but that expression levels can be impacted by both duplication of the region itself and inversion of other nearby regions, likely by disruption of regulatory domains.; Changed publications to: 35908152, 36928426
Limb disorders v2.64 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Brachydactyly was evident in 12/15 cases examined.
Limb disorders v1.127 LMBR1 Eleanor Williams changed review comment from: 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 is a sonic hedgehog (SHH) regulatory region of approx 800bp. It is not thought to affect the expression LMBR1.

Variants and duplications affecting the zone of polarizing activity regulatory sequence (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.; to: 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.
Limb disorders v1.127 LMBR1 Eleanor Williams changed review comment from: 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 is a sonic hedgehog (SHH) regulatory region of approx 800bp. It is not thought to affect the expression LMBR1.

Variants and duplications affecting the zone of polarizing activity regulatory sequence (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.

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.; to: 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 is a sonic hedgehog (SHH) regulatory region of approx 800bp. It is not thought to affect the expression LMBR1.

Variants and duplications affecting the zone of polarizing activity regulatory sequence (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.
Limb disorders v1.127 LMBR1 Eleanor Williams changed review comment from: Variants within the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene are thought to lead to Preaxial polydactyly. The ZRS is a sonic hedgehog (SHH) regulatory region. It is not thought to affect the expression LMBR1.

PMID: 31395945 - Xu et al 2019 - large 4 generation family with isolated preaxial polydactyly. A novel 446T>A ZRS) variant segregates with all PPD I–affected individuals. A knockin mouse with this ZRS variant exhibited
PPD I phenotype accompanying ectopic and excess expression of Shh.

PMID: 19847792 Wieczorek et al. (2010) - report 2 families (Turkish and Brazilian) with Werner mesomelic syndrome (hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet ) with variants in the ZRS region (404G>A and 404G>C). Two other families (families 3 and 4) were reported 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: 24965254 Norbnop et al. (2014) - report 2 Thai cases of Werner mesomelic syndrome, one familial with a heterozygous 406A>G variant in the ZRS and one sporadic with a heterozygous 404G>A ZRS mutation.

PMID: 24777739 - VanderMeer et al. (2014) - large 5-generation Mexican kindred where affect individuals (with isolated triphalangeal thumb, or preaxial polydactyly with triphalangeal thumbs) were heterozygous for a c.402C->T variant in ZRS region of LMBR1. A more severely affected daughter was homozygous for the same mutation.

Summary: > 3 cases where variants in the ZRS are found in patients with polydactyly. In 2 cases duplications covering parts of the ZRS were found in patients with polydactyly. 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.; to: 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 is a sonic hedgehog (SHH) regulatory region of approx 800bp. It is not thought to affect the expression LMBR1.

Variants and duplications affecting the zone of polarizing activity regulatory sequence (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.

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.
Limb disorders v1.58 EIF4A3 Eleanor Williams commented on gene: EIF4A3: Associated with Robin sequence with cleft mandible and limb anomalies (#268305) in OMIM and RICHIERI-COSTA-PEREIRA SYNDROME in Gene2Phenotype (confirmed, 5_prime or 3_prime UTR mutation).

PMID: 24360810 - Favaro et al. 2014 - found in Brazilian families with RCPS 17 affected probands were homozygous for the 16-repeat allele in the 5 prime UTR of EIF4A3, and 3 apparently unrelated affected individuals were compound heterozygotes (15 or 16 repeats). All tested parents were heterozygous for the 16-repeat allele, and unaffected siblings either lacked the expanded allele or were heterozygotes. The 15- and 16-repeat allele haplotypes spanning EIF4A3 are consistent with a common origin and corroborate their previous founder effect hypothesis for most Brazilian RCPS-affected individuals. Sequencing of EIF4A3 in five additional Brazilian affected individuals ascertained elsewhererevealed that four of them (, including 2 siblings) were homozygous for the 16-repeat allele. In contrast, the fifth (individual 25) was a compound heterozygote, possessing a 14-repeat allele in trans with a nucleotide change, c.809A>G, p.Asp270Gly. the c.809A>G mutation is embedded in a distinct haplotype, suggesting multiple pathogenic mutational origins in EIF4A3.
EIF4A3 transcript abundance was about 30%–40% lower in affected individuals than in controls in both cell types tested.
Zebrafish morpholinos show underdevelopment of craniofacial cartilage, bone alterations, and clefting of the lower jaw.
Limb disorders v1.45 STKLD1 Eleanor Williams changed review comment from: This gene is not in OMIM or Gene2Phenotype.

PMID: 30945277 - Umair et al 2019 - 2 consanguineous families of Pakistani origin segregating non‐syndromic pre‐axial polydactyly in autosomal recessive manner. The families originated from two different parts of Pakistan. Whole exome sequencing was used to identify the same homozygous variant c.84C > A, p.Tyr28* in both families that segregated with the condition. 2 affected and 5 unaffected family members were analysed. The variant was not found in homozygous state in ExAC, gnomAD, internal database, 1000 Genomes, EVS, dbSNP, and predicted to be damaging in online available tools used for bioinformatics analysis. However, a minor allele frequency of 0.001119 for the variant was noted in the South Asian population.; to: This gene is not in OMIM or Gene2Phenotype.

PMID: 30945277 - Umair et al 2019 - 2 consanguineous families of Pakistani origin segregating non‐syndromic pre‐axial polydactyly in autosomal recessive manner. The families originated from two different parts of Pakistan. Whole exome sequencing was used to identify the same homozygous variant c.84C > A, p.Tyr28* (NM_153710.3) in both families that segregated with the condition. 2 affected and 5 unaffected family members were analysed. The variant was not found in homozygous state in ExAC, gnomAD, internal database, 1000 Genomes, EVS, dbSNP, and predicted to be damaging in online available tools used for bioinformatics analysis. However, a minor allele frequency of 0.001119 for the variant was noted in the South Asian population.

The transcript mentioned in this paper NM_153710.3 is linked to GeneID:169436, HGNC:28669 which is STKLD1 (previous name C9orf96).
Limb disorders v1.44 GLI3 Eleanor Williams commented on gene: GLI3: PMID: 31115189 - Umair et al 2019 - report a five generation Pakastani kindred having 12 affected individuals exhibiting nonsyndromic postaxial polydactyly type A condition. Using exome sequencing in the three affected individuals, they identified a novel heterozygous frameshift variant (c.3567_3568insG; p.Ala1190Glyfs*57) in the transcriptional activator (TA2) domain of GLI3. The variant segregates with the disease phenotype in all members of the family. The variant was not observed in the ExAC browser, gnomAD, 1,000 Genomes, Pakistan Genetic Mutation database (Qasim et al., 2018) and in 135 in‐house exomes (Pakistani exomes).