A number sign (#) is used with this entry because of evidence that Roifman-Chitayat syndrome (ROCHIS) is caused by the simultaneous occurrence of homozygous mutations in 2 different genes: PIK3CD (602839) on chromosome 1p36 and KNSTRN (614718) on chromosome 15q15. One such family has been reported.

Roifman-Chitayat syndrome (ROCHIS) is an autosomal recessive digenic disorder characterized by global developmental delay, variable neurologic features such as seizures, ataxia, and optic atrophy, dysmorphic facial features, distal skeletal anomalies, and combined immunodeficiency manifest as recurrent infections (summary by Sharfe et al., 2018).

Roifman and Chitayat (2009) reported 2 sisters, born to second-cousin parents, with a syndrome characterized by combined immunodeficiency, facial dysmorphism, optic atrophy, distal skeletal anomalies, hypotonia, and global developmental delay. Both had ataxia, and 1 had myoclonic seizures. Both patients had repeated bacterial, viral, and fungal infections consistent with combined immunodeficiency. Evaluation of the immune system revealed depressed responses to mitogens or anti-CD3 antibody. Humoral immunity was also affected as both patients failed to mount an antibody response to vaccination. Sharfe et al. (2018) reported follow-up of these sisters, who were 20 and 14 years of age, respectively. Both patients remained developmentally delayed with significant cognitive, speech, and motor retardation; 1 had progressive tremor and ataxia. Laboratory studies showed hypogammaglobulinemia, poor response to vaccination, borderline B cell levels, and low NK cell levels. In vitro studies showed impaired responses to mitogens and antigens, suggesting involvement of both the B- and T-cell lineages. Abnormalities in patient B cells showed compromised survival or proliferation of differentiated B cells, and T cells showed impaired activation after TCR stimulation.

Roifman and Chitayat (2009) suggested autosomal recessive inheritance for this disorder because of its occurrence in female sibs of consanguineous parents. The molecular findings of Sharfe et al. (2018) indicated autosomal recessive digenic inheritance of ROCHIS.

By linkage analysis, Roifman and Chitayat (2009) identified maximum lod scores for the disorder in their family to chromosomes 1 and 15 (maximum lod score of 2.654). The disease locus was mapped either to a 14-cm interval between SNPs rs11583804 and rs11806366 on chromosome 1p36.23-p33, or to a 37-cm interval between SNPs rs2732029 and rs815198 on chromosome 15q11-q21.1.

In 2 sibs, born of consanguineous parents, with ROCHIS originally reported by Roifman and Chitayat (2009), Sharfe et al. (2018) identified homozygous loss-of-function mutations in 2 different genes: PIK3CD (602839.0005) and SKAP (KNSTRN; 614718.0001). The mutations, which were found by whole-genome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed no detectable PIK3CD or KNSTRN proteins, consistent with a loss of function of both genes. Patient cells showed a near absence of AKT (164730) phosphorylation compared to controls, revealing defective PIK3CD function. Detailed in vitro studies showed that patient-derived B and T lymphocytes failed to cluster or aggregate properly, similar to abnormalities noted in SKAP-null cells, suggesting that SKAP deficiency was responsible for this feature. In addition, T cells showed reduced spontaneous migration and inefficient cell-cell contact formation due to limited cell spreading. These abnormalities were associated with aberrant MAP4 (157132) distribution and localized altered microtubule acetylation, which was attributed to loss of SKAP. Sharfe et al. (2018) concluded that the complex phenotype resulted from the concurrent loss of 2 different genes, each of which contributed to the disease manifestations.