Deletion of the ANKRD15 Gene at 9p24.3 Causes Parent-of-origin-dependent Inheritance of Familial Cerebral Palsy

A four-generation family was studied in which nine children had congenital cerebral palsy (CP), characterized by quadriplegia and mental retardation. All the affected children were born to healthy, related fathers, whereas the children of their healthy female relatives were unaffected. Linkage analysis attributed the condition to chromosome 9p24.3, where a 225 kb deletion was identified. The deletion spans a single gene, ANKRD15 (ankyrin repeat domain 15), which is ubiquitously expressed. In the affected children, the ANKRD15 is not expressed in lymphoblastoid cells, whereas in their healthy fathers, who harbor the same deletion, the expression of ANKRD15 did not deviate from controls. This expression pattern can be interpreted as a maternal imprinted gene that is expressed only from the paternal allele. The expression of ANKRD15 in lymphoblastoid cells from the control group was monoallelic but not imprinted. The monoallelic expression was restricted to the ANKRD15 gene, whereas biallelic expression was found in the DOCK8 gene, which resides at the telomeric side of the deletion. No correlation was found between the expression of the ANKRD15 gene and the pattern of DNA methylation in the CpG islands 5' of the gene. However, differences in methylation pattern were found in the CpG islands flanking the DMRT1 gene, which is located at the 3' side of the ANKRD15 gene. In the affected individuals, as in the control group, the CpG islands were hypo-methylated, whereas in the healthy fathers, the CpG islands were hyper-methylated in cis with the deletion. This unique family demonstrates a phenomenon of a deletion that creates imprinting-like inheritance. The implication of this family to sporadic CP is discussed.