Multigene deletions on chromosome 20q13.13-q13.2 includingSALL4 result in an expanded phenotype of Okihiro syndrome plus developmental delay

Abstract

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.

Activity-Dependent Neuroprotective Protein Snippet NAP Reduces Tau Hyperphosphorylation and Enhances Learning in a Novel Transgenic Mouse Model

“…Studies in other laboratories indicated that deletions in the human ADNP chromosomal region (20q12-13.2; Zamostiano et al, 2001) may be associated with mental retardation in man (Borozdin et al, 2007). Most recently, a reduction in the ADNP mRNA levels was observed in the cerebral cortex and astrocytes from prenatal ethanol-exposed rat fetuses.…”

Severe Phenotype in a Girl with Partial Tetrasomy 7, Karyotype 46,XX,trp(7)(q35q36)

“…As an internal control, a probe derived from 14q32.33 (locus D14S1420) was also hybridized. Array CGH testing (Agilent 105 K microarray, Agilent Technologies, Palo Alto, Calif., USA) was performed from peripheral venous blood as described [Borozdin et al, 2007]. Briefly, 3 g genomic DNA of the patient and of a reference sample were each digested with Alu I and Rsa I, heat inactivated and verified by agarose gel electrophoresis.…”

Duplication 8q12: confirmation of a novel recognizable phenotype with duane retraction syndrome and developmental delay

“…According to the London medical database the association of DRS with developmental delay as been observed in few patients in around nine entities including six syndromes (ie, Bardet Biedl syndrome (OMIM 209900), 4 Blepharophimosis Ptosis Epicanthus Inversus Syndrome(OMIM 110100), 5 Goldenhar syndrome (OMIM 164210), 6 Moebius syndrome (OMIM 157900), 7 Wildervanck syndrome (OMIM 314600) 8 and Athabascan brainstem dysgenesis syndrome (OMIM 601536) 9 ), foetal alcohol syndrome, 10 and several chromosomal anomalies namely 12q12 microdeletion 11 and 20q13.13-13.2 deletion. Clinical features associated with the 20q13.13-13.2 deletion are probably due to a contiguous gene deletion encompassing the SALL4 gene responsible for Okihiro syndrome (DRS, renal deficiency and limb features) 12 and other genes responsible for intellectual disability.…”