SALL4

• Haploinsufficiency score: 3
• Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
• Haploinsufficiency Phenotype: DUANE-RADIAL RAY SYNDROME; DRRS

Evidence for haploinsufficiency phenotype

PubMed ID	Description
16086360	Kohlhase J et al. (2005) described 17 previously published and 5 novel pathogenic SALL4 variants associated with disease in patients with acro-renal-ocular syndrome or Duane radial-ray syndrome (i.e., Okihiro syndrome). All the described SALL4 variants were loss of function (8 nonsense and 14 frameshift).
30552424	Vanlerberghe C et al. (2019) sequenced SALL4 in patients originally diagnosed with Holt-Oram syndrome but lacking causative TBX5 variants. Eight patients were found to carry loss-of-function (8 frameshift and 2 nonsense) SALL4 variants and were thus re-diagnosed with Duane-radial ray syndrome (i.e., Okihiro syndrome).
17256792	Paradisi I and Arias S (2007) investigated a large multigenerational family with autosomal dominant IVIC syndrome. A frameshift variant in SALL4 was identified that segregated with disease among the 29 family members assessed (14 affected and 15 unaffected).

Haploinsufficiency phenotype comments:

SALL4 variants are associated with Duane radial-ray syndrome (i.e., Okihiro syndrome; OMIM # 607343), IVIC syndrome (OMIM # 147750), and acro-renal-ocular syndrome (AROS), as well as potentially Holt-Oram syndrome (HOS; OMIM # 142900; associated with pathogenic TBX5 variants). These phenotypes have overlapping features and display intra- and inter-family variability. For more information, see Borozdin W et al. (2004), Kohlhase et al. (2005), and GeneReviews (PMID: 15286162, 16086360, 20301547). Additional evidence includes: PMID: 15286162 Borozdin W et al. (2004) sequenced exons 1-4 of SALL4 in genomic DNA obtained from 5 families with SALL4-related disorders, including 2 families with acro-renal-ocular syndrome. Loss-of-function SALL4 variants (2 nonsense and 5 frameshift) were found to segregate with disease in the members available for testing in all 5 families. PMID: 12395297 Al-Baradie R et al. (2002) sequenced 4 exons of SALL4 in 3 families presenting with multi-generational Duane radial-ray syndrome. Disease within all three of these families was found to segregate with loss-of-function SALL4 variants, 2 of which were frameshift and 1 was nonsense. Additional publications describing SALL4 loss-of-function variants associated with SALL4-related disorders include Kohlhase et al. (2002), Borozdin W et al. (2004), and Kohlhase et al. (2005) (PMID: 12843316, 15342710, 16086360).

• Triplosensitivity score: 0
• Strength of Evidence (disclaimer): No evidence for dosage pathogenicity