ClinVar Genomic variation as it relates to human health

This CNV is a 1.4 Mb deletion of 17p13.3-p13.2 on chromosome 17, (seq[GRCh37]del(17)(p13.3p13.2); chr17:g.2313096_3735525del), found in a de novo state. This event encompasses 35 genes, including the PAFAH1B1 gene (formerly known as LIS1), and partially overlaps with the well-described 17p13.3 microdeletion region. This event does not include the YWHAE gene, which is also generally deleted in individuals with 17p13.3 microdeletion syndrome and extends proximally into the adjacent band, 17p13.2. Microdeletions of 17p13.3 are associated with a range of clinical phenotypes, including isolated lissencephaly sequence (ILS), subcortical band heterotopia (SBH) and Miller-Dieker syndrome (MDS) (Dobyns et al. 2014). The MDS phenotype is generally attributed to haploinsufficiency of minimal critical region which encompasses both PAFAH1B1 and YWHAE, however several surrounding genes have also been identified as potential contributors to the presentation (Cardoso et al. 2003, Dobyns et al. 2014). Deletions and loss-of-function variants in PAFAH1B1 typically cause ILS and heterozygous deletions containing PAFAH1B1 and small loss-of-function variants have been reported in over 60 individuals with lissencephaly (Cardoso et al. 2002, Cardoso et al. 2003, Dobyns et al. 2014). The majority of the 17p13.3 deletions described in the literature occurred de novo and approximately 20% are inherited from a parent who carries a balanced chromosome rearrangement (Dobyns et al. 2014). This event also fully encompasses two genes associated with autosomal recessive disorders in which loss of function is a mechanism of disease, ASPA and CTNS, which are associated with Canavan disease and cystinosis respectively. Based on the collective evidence, this CNV is classified as pathogenic.