Intellectual Developmental Disorder With Short Stature And Variable Skeletal Anomalies

A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with short stature and variable skeletal anomalies (IDDSSA) is caused by homozygous mutation in the WIPI2 gene (609225) on chromosome 7p22. One such family has been reported.

Clinical Features

Jelani et al. (2019) reported a large consanguineous Pakistani family in which 6 individuals had a similar complex neurodevelopmental disorder. Two adult patients were described in detail. Features included severely impaired intellectual development with low IQ, speech and language impairment, and delayed acquisition of fine and gross motor milestones. Brain imaging showed global brain volume loss. Skeletal abnormalities included short stature, camptodactyly, fifth finger clinodactyly, thumb hypoplasia, overlapping toes, and kyphosis or lumbar vertebral abnormalities. ECG showed variable cardiac arrhythmias that were not clinically significant; echocardiograms were normal. Both patients also had subclinical hypothyroidism. Additional features included dyskinesia, dysarthria, and both calm and playful behavior.

Inheritance

The transmission pattern of IDDSSA in the family reported by Jelani et al. (2019) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from a highly consanguineous Pakistani family with IDDSSA, Jelani et al. (2019) identified a homozygous missense mutation in the WIPI2 gene (V249M; 609225.0001). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Two additional family members were affected, but DNA was not available for study. Fibroblasts derived from one of the patients showed impaired stress-induced formation of autophagosomes, with reduced WIPI2 puncta, reduced LC3 (MAP1LC3A; 601242) lipidation, and reduced autophagic flux compared to controls. In vitro functional expression studies in transfected HEK293 cells showed that the mutation significantly reduced the interaction of WIPI2 with other genes involved in autophagy, including ATG16L1 (610767); however, these abnormalities were not apparent in patient cells.