Multigene deletions on chromosome 20q13.13-q13.2 including SALL4 result in an expanded phenotype of Okihiro syndrome plus developmental delay.

Okihiro syndrome results from truncating mutations in the SALL4 locus on the chromosome 20q13.13-q13.2. Deletions of the whole SALL4 coding region as well as single exon deletions are also a common cause of Okihiro syndrome and indicate haploinsufficiency as the disease causing mechanism. The phenotypes caused by SALL4 deletions are not different from those caused by point mutations. No multigene deletion including SALL4 has been documented to date. Here we report the detection and molecular characterization of four novel, overlapping microdeletions, all spanning SALL4 and flanking genes, in four unrelated cases with features of Okihiro syndrome and variable degrees of psychomotor delay. All deletions were first identified and mapped by quantitative Real Time PCR. Subsequently, three of four deletions were mapped in further detail by high-resolution array CGH (244k oligo-arrays). All cases had larger deletions of varying size (1.76-1.78 Mb, 2.01-2.05 Mb, 2.16-2.17 Mb, and 1.3-2.8 Mb, respectively), which included SALL4 plus 3 to 7 additional functional genes. While three cases with largely overlapping deletions are mildly developmentally delayed, the only patient with a more centromeric deletion is clearly mentally retarded. In this patient, four genes (MOCS3, DPM1, ADNP, BCAS4) are deleted, which were not affected in the other three cases, suggesting that the deletion of one or more of these genes contributes to the mental retardation. Since two of the four cases presented with choanal atresia, large deletions including SALL4 should be considered in the differential diagnosis of children with suspected CHARGE syndrome but without detectable CHD7 mutations.

Diagnostic proceeding in Silver-Russell syndrome.

BACKGROUND: Silver-Russell syndrome (SRS) describes a uniform malformation syndrome characterized by pre- and postnatal growth restriction (<3rd percentile) and a typical craniofacial gestalt. The basic defect of SRS is currently unknown, and the number of meaningful genetic tests available is therefore limited. Different chromosomal aberrations have been identified, including in the chromosomal region 7p12-p14. Detailed analyses of numerous candidate genes have not revealed any relevant insights with respect to the etiology of the disease.However, maternal uniparental disomy (UPD) of chromosome 7 (matUPD7), the inheritance of both homologues of chromosome 7 only from the mother, is observed in approximately 10% of SRS patients. Here, we report on our experiences of UPD testing in patients referred to our laboratory with the clinical diagnosis of SRS. A diagnostic algorithm for SRS is suggested. METHODS: Eighty-six patients with the clinical diagnosis of SRS were screened for matUPD7 by microsatellite typing. In 13 cases, the clinical data were consistent with the diagnosis of SRS. The other 73 patients were referred for UPD testing with the suspected diagnosis of SRS, but clinical data were scarce. RESULTS: In total, we identified three new cases of matUPD7: one patient belonged to the cohort of 13 clinically characterized patients; the other two patients were referred with the suspected diagnosis of SRS but initially without detailed reports. DNA studies revealed uniparental heterodisomy 7 in two patients, while the results in the third case were consistent with uniparental isodisomy. CONCLUSIONS: MatUPD7 is predominantly detectable in patients showing SRS features, and testing should therefore be restricted to this group of growth-restricted patients. Generally, a combination of cytogenetic and molecular genetic tests can be offered in SRS, aiming at the detection of chromosomal rearrangements and matUPD7 in >10% of SRS patients.