ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000012.11) (NC_000012.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
20170896 Klopocki et al. 2010 describe mutations in PTHLH in five unrelated families with brachydactyly type E (BDE). The mutations include: 1) K120X nonsense mutation; 2) pX178WextX*54 non-stop mutation (authors propose nonstop-mediated decay as mechanism of LOF); 3) L60P missense mutation (authors performed functional test of overexpressing WT and mutant contructs in chicken limb micromass cultures. The authors used alkaline phosphatase activity as the indicator of differentiation. The mutant allele had a weaker suppression of ALP activity; therefore, the authors proposed LOF); 4) L44P missense mt (this mutant was not functionally tested); 5) 907 kb deletion including this gene and 5 others. The 4 single nucleotide changes were not found in 200 control individuals.
30458061 Reyes et al. 2018 (PMID: 30458061): The authors describe a female proband with brachydactyly type E (BDE) and no evidence for abnormal calcium or phosphate regulation. Whole exome sequencing (WES) revealed "a novel heterozygous A>G change at nucleotide -3 up-stream of PTHLH exon 3 that encodes the last two amino acids of the pro-sequence and the mature PTHrP...[resulting in] a heterozygous insertion of genomic nucleotides -2 and -1 causing a frame-shift after residue 34 of the preprosequence and thus 29 novel residues without homology to PTHrP or any other protein." This variant was also found in her affected mother, maternal aunt, and monozygous twin sons, but not in her unaffected daughter or sister.
29947179 Bae et al. 2018 (PMID:29947179): The authors describe a male proband with BDE and normal calcium and phosphate levels. WES of the proband, his affected mother, and his unaffected father revealed a shared c.169C>T (p.Arg57*) variant for the proband and his affected mother. The family history indicates that there are at least 7 other affected relatives across 4 generations of the family, though no other individuals were tested.

Haploinsufficiency phenotype comments:

Additional Evidence: Thomas-Teinturier et al. 2016 (PMID: 26640227): The authors describe a female proband with BDE and no reported family history. Single gene sequencing of PTHLH was peformed, and a heterozygous de novo deletion was detected (c.101+3delAAGT). Per the authors, "this alteration deletes four nucleotides from position 3?6 of intron V...[it] is predicted to cause a moderate decrease in the consensus sequence value of the natural donor splice site (WT 84.38; Mut 60.23; Var.% 28.62). As a result, novel additional potential donor sites with a higher consensus value could be created. Use of these sites is predicted to lead to aberrant transcripts with a premature stop codon, as in the first family." Parental relationships were not confirmed. The authors also presented a female proband and her mother with BDE. Single gene sequencing of PTHLH was performed. A heterozygous deletion, c.47_101+73del128 "compris[ing] bases 47?101 of exon V and 73 bases of intron V (total deletion: 128 bp)" was found in the proband and her mother (NM_198965.1). Per the authors: "The c.47_101?73del128 defect removes the canonical donor site of exon V. Consequently, new potential splice sites localized before or after the deletion breakpoint are predicted to be used. These aberrant splicings are expected to produce transcripts with premature stop codon 5' to the last 50 nucleotides of the penultimate exon [Holbrook et al., 2004], which are predicted to be degraded by nonsense-mediated mRNA decay." Pereda et al. 2017 (PMID: 28211986): The authors describe a female proband with BDE and no reported family history. Single gene sequencing of PTHLH revealed a heterozygous c.166C>T (p.R56*) variant; this variant has been described in an unrelated individual with BDE by Jamsheer et al. 2016. The variant was also detected in a mosaic state in the girl's unaffected father (10-20% of blood cells, not detected via buccal swab or hair sample). Jamsheer et al. 2016 (PMID: 26763883): The authors describe a female proband with BDE and no reported family history. Single gene sequencing of PTHLH revealed a heterozygous c.166C>T (p.R56*) variant; this variant has been described in an unrelated individual with BDE by Pereda et al. 2017. This variant was said to be de novo, but no information regarding confirmation of parental relationships was presented. The authors also presented a female proband with BDE; her full sister and father were also reported to be affected. Single-gene sequencing revealed a NM_198965.1 c.258delC (p.N87Tfs*18) in exon 4 of PTHLH in the proband and her affected family members, but not in her unaffected mother, sister, or paternal aunt. Maass et al 2010 (PMID: 20015959) report a translocation in a patient with Brachydactyly Type E (BDE). The translocation t(8;12)(q13;p11.2) breakpoints are upstream of PTHLH and within KCNB2 on 8q13. The authors used functional studies to show that the derivative chromosome decreased PTHLH activity, thus suggesting downregulation of PTHLH as a cause of BDE. Maass et al (2012, PMID:23093776) report more information on this patient as well as another patient with a t(4;12)(q13.2q13.3;p11.2) and discuss complex findings including the effects of enhancers working in cis and trans on multiple targets.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
26733284 Flottmann et al. 2016 describe 4 individuals across three generations of a family affected with "short humerus, curved radius, and a specific pattern of hand bone abnormalities, namely extremely short and misshaped metacarpals and middle phalanges with disturbed epiphyseal maturation." ArrayCGH revealed a 70kb duplication in the proband encompassing only the PTHLH gene (arr[hg19] 12p11.22 (28082255?28152554) ? 3 (minimal positions)). The duplication segregated with affected status in the family, and was not found in the two unaffected individuals available for testing.

Triplosensitivity phenotype comment:

Collinson et al. 2010 (PMID: 21082660) report a patient with mesomelic limb shortening and symmetrical enchondromatosis and found a de novo duplication including 12 genes of which PTHLH is involved. Gray et al. 2014 (PMID: 25007883) describe two additional families with acro-osteolysis, bowed long bones, and metaphyseal lesions and multi-gene duplications involving PTHLH.