ClinGen Dosage Sensitivity Curation Page

PAFAH1B1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000017.10) (NC_000017.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11754098 Cardoso et al. (2002) provide a variant update on PAFAH1B1 (LIS1), including intragenic variants from 41 patients with lissencephaly (4 from the current report and others from previous publications). Thirty-six of the 41 variants "result in a truncated or internally deleted protein." Six de novo nonsense variants are included in this publication.
19667223 Saillour et al. (2009) describe 31 heterozygous PAFAH1B1 variants and 8 small intragenic deletions in individuals with lissencephaly. Of the 31 point variants, 12 were nonsense, 8 were frameshift, and 5 were splicing defect variants. The 8 intragenic deletions ranged from 1 exon to almost the entire gene (exons 2-11).

Haploinsufficiency phenotype comments:

Loss of PAFAH1B1 (previously known as LIS1) is associated with lissencephaly. Larger deletions involving PAFAH1B1 and other genes at the 17p13.3 locus are associated with Miller-Dieker syndrome, which includes lissencephaly (often more severe than observed with PAFAH1B1 point variation) and other features, such as facial dysmorphisms. For a full description of the evidence supporting the 17p13.3 region, see ISCA-37430. See GeneReviews for additional information on PAFAH1B1-related lissencephaly. Of note, Bruno et al. (2010) further characterize genotype and phenotype correlations within the 17p13.3 microdeletion and microduplication region (PMID:20452996).

Triplosensitivity phenotype comment:

PAFAH1B1 is located within the 17p13.3 duplication syndrome with developmental delay and other features (PMID:19520700 Roos et al. 2009). PMID:19136950 Bi et al. (2009) reported on 7 patients with duplications in 17p13. Four patients have duplications including YWHAE, two patients have gains including PAFAH1B1, and one patient has a gain that includes both genes. Subjects 5 and 6 have gains of PAFAH1B1 (and not YWHAE), but there are also 6 additional genes in these imbalances. Based on phenotype comparisons of patients with YWHAE duplications versus PAFAH1B1 duplications, the authors suggest that gain of PAFAH1B1 causes subtle brain abnormalities, developmental delay, and relative microcephaly. For a full description of evidence related to the 17p13.3 region, see ISCA-37430.