ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000005.9) (NC_000005.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
15654336 Entesarian et al. (2005) report 16 individuals from two extended families of Swedish origin with full penetrant aplasia of lacrimal and salivary glands (ALSG). The 12 affected members of family 1 (4 generations) had a 53 kb deletion including exons 2 and 3, without the involvement of any flanking genes. In family 2 (3 generations) , a nonsense variant in exon 3 (R193X; c.577C>T) was identified in the four affected members.
16630169 Milunsky et al. (2006) identified a nonsense mutation (K137X) in exon 2 of FGF10 (Family 2) in a 19-year-old mother with ALSG and her 2-year-old daughter with Lacrimoauriculodentodigital (LADD) syndrome. This variant was not found in 200 controls. The author concluded that ALSG and LADD syndrome may represent variable presentations of the same clinical spectrum caused by FGF10 mutations.
19102732 Scheckenbach et al. (2008) identified the 1st splicing variant (c.430-1 G>A) in FGF10 gene, which led to an alternative acceptor site for exon 3 and premature stop codon, in 2 affected brothers with ALSG, but not in 193 controls. Patients? father, grandma and grandaunt were all affected, but not available for testing. Deceased relatives showed no additional features of LADD.

Haploinsufficiency phenotype comments:

4. Seymen et al. (2017) (PMID: 26955834) identified a nonsense variant (c.237G>A) in exon 2 in a 4 yro boy, his 8 yro sister and the mother (Turkish family), all affected with ALSG. Haploinsufficiency score is regarding ALSG and LADD, which present with phenotypic overlap. Additional evidence suggests that heterozygosity for LOF variants in FGF10 may result in pulmonary phenotypes (an extension of the ALSG/LADD phenotypic spectrum), while compound heterozygous variants may result in a more severe lung phenotype: Klar et al. (2011) (PMID: 21742743) studied the extended familes with ALSG from Etesarian et al. (2005), looking for the role of FGF10 in the development and function of the lungs and a predisposition to chronic obstructive pulmonary disease (COPD). In fact, FGF10 insufficient patients showed non-reversible airway obstruction when compared with both predicted reference values and siblings with normal FGF10 alleles, supporting that FGF10 haploinsufficiency is associated with reduced pulmonary function consistent with COPD. Korolak et al. (2019) (PMID: 30639323): To elucidate the genetic cause of human lung development, a total of 26 deceased patients from 23 families with lethal developmental lung disease were tested by microarray, WGS and WES. 5 affected individuals from 4 families were found to be comp het for coding variants ( including 2 large overlapping deletions, a ns c. 577C>T and a fs c.526delA) and a SNV in the noncoding region of FGF10. All het carriers of the coding variants including carrier parents have LADD, however without lung phenotype, while het carriers of the noncoding variants were healthy. Since FGF10 haploinsufficiency can not explain the lung phenotype, the data supported the pathogenicity of FGF10 compound heterozygosity. There have also been reported heterozygous LOF variants in cohorts analyzed for other phenotypes: Silversides et al. (2012) (PMID: 22912587) did microarray analysis on a cohort study of 433 patients with Tetralogy of Fallot and/or pulmonary atresia and identified a patient with a small deletion (135kb) involving the entire FGF10 gene. The patient did not meet criteria for LADD syndrome or ALSG. Lee et al. (2017) (PMID: 29215649) performed a 20-gene massive parallel sequencing panel (including FGF10 gene) on 309 Australian and New Zealand patients with craniosynostosis and identified a nonsense variant and a frameshift variants in 2 patients.

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