Mental Retardation, X-Linked 91

Clinical Features

Gustavson et al. (1984) reported a girl with a developmental history and features typical of Prader-Willi syndrome (PWS; 176270), including muscular hypotonia that was severe in infancy, pronounced early childhood obesity, small hands and feet, shortness of the fifth fingers relative to the other digits, facial changes, and retarded psychomotor development. She did not have short stature; the authors commented that patients with PWS occasionally have normal stature until later childhood.

The patient previously reported by Gustavson et al. (1984) was reexamined at 29 years of age by Mansouri et al. (2005), at which time they reported that her PWS-like features had disappeared with age. She was no longer obese, but was of average height and weight, and had severe psychomotor retardation with an IQ of 30. She had epileptic seizures beginning at 4 years of age. She had a dysmorphic facial appearance with a small nose, epicanthal folds, high-arched palate, large front teeth, low posterior hairline, small hands with clinodactyly of the fifth fingers, and small feet in planovalgus position. She was unable to speak and required help with daily self-care.

Cytogenetics

In a girl with psychomotor retardation and normal stature, Gustavson et al. (1984) identified a de novo balanced translocation, t(X;15)(q21.2;p12). Using FISH, Mansouri et al. (2005) further defined the breakpoints in this patient to t(X;15)(q13.3;cen). The breakpoint on chromosome 15 was located at least 4.5 Mb centromeric of the PWS region and a normal hybridization pattern was found using the probe PW71. The Xq13.3 breakpoint was localized to within 3.9 kb of the first exon of the ZDHHC15 gene, and ZDHHC15 transcript was absent from the patient's lymphocytes. Methylation studies showed a 100% skewed X inactivation in patient-derived lymphocytes, indicating that the normal X chromosome was inactive.

Moyses-Oliveira et al. (2015) reported a 42-year-old woman (patient 3) with normal hallmark developmental milestones and primary amenorrhea who had an apparently balanced translocation between chromosomes X and 9: 46,X,t(X;9)(q13;p11.1). The X-chromosomal breakpoint disrupted the ZDHHC15 gene at intron 10. No ZDHHC15 gene expression was detected in the patient's peripheral blood, whereas all controls presented normal expression levels. A WAIS-III test at age 41 years revealed that the patient had an IQ of 111, indicating that the ZDHHC15 gene in not involved in intellectual disability.