ROR2 – Brachydactyly Type B1

Autosomal dominant brachydactyly type B1 (BDB1) is characterized by terminal deficiency of the distal phalanges and nails. Heterozygous truncating variants in the receptor tyrosine kinase-like orphan receptor 2 gene (ROR2) underlie BDB1 by producing C-terminally truncated proteins that disrupt normal digit development. The inheritance is autosomal dominant with complete penetrance of limb anomalies.

Genetic evidence includes five unrelated pedigrees harboring ROR2 truncating alleles. A large Punjabi‐speaking Pakistani family exhibited 34 affected individuals segregating the nonsense mutation c.2278C>T (p.Gln760Ter) (PMID:23238279) with full co-segregation. A Chinese kindred was linked to ROR2 and carried c.2243delC (p.Trp749GlyfsTer25) (PMID:19461659). Additional heterozygous deletions, including c.1396_1398delAA (p.Lys466LysfsTer57) (PMID:24954533), c.2273C>A (p.Ser758Ter) (PMID:25696018), and c.1320dupG (p.Arg441AlafsTer18) (PMID:36064339), were each observed in single pedigrees with segregation and absence in controls.

The variant spectrum is dominated by heterozygous frameshift and nonsense mutations clustering in the distal kinase domain and C-terminal tail, predicting loss of the intracellular signaling region. No missense or splice variants have been recurrently reported in BDB1. Founder effects have not been described to date.

Functional studies demonstrate that truncating BDB1 mutants escape nonsense-mediated decay, localize to the plasma membrane, and interfere with chondrocyte differentiation. Chick limb assays overexpressing human BDB1 alleles disrupt growth plate architecture and block chondrocyte maturation (PMID:17061261). Cell line experiments quantifying membrane versus endoplasmic reticulum distribution of ROR2 mutants reveal stable expression and membrane targeting for BDB1 alleles, correlating with dominant digit truncation (PMID:19640924).

There is no conflicting evidence disputing ROR2 in BDB1. Distinct phenotypes arise from recessive loss-of-function alleles in upstream exons causing Robinow syndrome, whereas downstream truncations produce dominant BDB1 by a gain-of-function or dominant-negative mechanism.

Integrating genetic segregation, variant clustering, and concordant functional disruption, the association between ROR2 and BDB1 meets ClinGen Strong criteria. ROR2 genetic testing is therefore clinically useful for diagnosis of terminal phalangeal hypoplasia and informs recurrence risk counseling.

Key take-home: Heterozygous truncating ROR2 variants are a definitive molecular cause of autosomal dominant brachydactyly type B1, enabling precision diagnosis and family planning.

References

• Journal of human genetics | 2009 | A novel single-base deletion in ROR2 causes atypical brachydactyly type B1 with cutaneous syndactyly in a large Chinese family. PMID:19461659
• Clinical dysmorphology | 2013 | A nonsense mutation in the gene ROR2 underlying autosomal dominant brachydactyly type B. PMID:23238279
• Gene | 2014 | A new mutation in the gene ROR2 causes brachydactyly type B1. PMID:24954533
• PLoS genetics | 2015 | Candidate gene screening of IHH and ROR2 in brachydactyly subtypes. PMID:25696018
• BMC Pediatrics | 2022 | A novel variant in the ROR2 gene underlying brachydactyly type B: a case report. PMID:36064339
• Developmental dynamics | 2006 | Cloning and expression pattern of chicken Ror2 and functional characterization of truncating mutations in Brachydactyly type B and Robinow syndrome. PMID:17061261
• Human molecular genetics | 2009 | A gradient of ROR2 protein stability and membrane localization confers brachydactyly type B or Robinow syndrome phenotypes. PMID:19640924

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