ClinGen Dosage Sensitivity Curation Page

2p21 region (includes PREPL and SLC3A1)

  • Curation Status: Complete


Location Information

Select assembly: (NC_000002.11) ()
  • Haploinsufficiency score: Gene associated with autosomal recessive phenotype
  • Strength of Evidence (disclaimer): Gene associated with autosomal recessive phenotype
  • Haploinsufficiency Phenotype: HYPOTONIA-CYSTINURIA SYNDROME
Evidence for haploinsufficiency phenotype
PubMed ID Description
11524703 Pavari et al. describe one consanguinous Bedouin family; 2 generations affected; 9 affecteds. Region first suspected by linkage, deletion first suspected by multiple PCR failures across SLC3A1. Further PCR studies established the deletion size at ~179 kb, including the PREPL gene, as well as SLC3A1, PP2C?, and C2orf34. All parents were heterozygous for the deletion. A description of the transcription product can be found at PMID:15913950.
16385448 Jaeken et al. describe 11 patients from 9 reportedly unrelated families from Belgium and France. 4 different sized deletions were found, each involving only SLC3A1 and PREPL (not the other two genes mentioned in the reference above). Patients were either homozgyous or compound heterozygous for these particular deletions. Heterozygous deletions were found in each of the parents, when available. Expression studies in one patient revealed normal expression patterns for PP2C? and C2orf34, the other two genes implicated in the earlier report.
18234729 Chabrol et al. describe 2 patients from 1 reportedly nonconsanguinous Moroccan family. ~77 kb deletion fine-mapped using qPCR. The breakpoints of the deletion, referred to as deletion F, are located in SLC3A1 intron 4 at position 23330027228 (genome assembly 36.2,NCBI) and C2orf34 intron 1 at position 2340761262. PREPL is completely deleted. Due to a lack of parental DNA, homozygosity for deletion F in both siblings was determined using microsatellite markers spanning a genomic region over 1 Mb. Homozygosity for the five microsatellites was observed, indicative for the presence of deletion F on both alleles.

Haploinsufficiency phenotype comments:

Please note that this phenotype has been associated with homozygous deletions. There are thought to be at least 6 common deletions that contribute to this phenotype (PMID:17579669). Abnormal phenotypes were not reported for the parents of these individuals, carriers of the heterozygous deletions.

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