Integrated analysis of clinical signs and literature data for the diagnosis and therapy of a previously undescribed 6p21.3 deletion syndrome.
A de novo 0.3 Mb deletion on 6p21.3 was detected by array-comparative genomic hybridization in a girl with mental retardation, drug-resistant seizures, facial dysmorphisms, gut malrotation and abnormal pancreas segmentation. Consistent with phenotypic manifestations is haploinsufficiency of SYNGAP1, which was recently demonstrated to cause non-syndromic mental retardation, and of the flanking genes CuTA, a likely modulator of the processing and trafficking of secretory proteins in the human brain, and hPHF1, involved in HOX gene silencing. Mutations of both CuTA and hPHF1 were never reported as causative of human diseases. Similarly, the present syndromic condition was not previously described and it can be regarded as a human model confirming the suggested biological properties of the genes included in the deletion interval. In addition, experimental evidence that SYNGAP1 and CuTA are involved in the secretory pathway in neurons, through glutamate and acetylcholinesterase signalling, prompted us to consider modulation of the glutamate pathway as target of a therapeutic strategy for seizure control.
Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Policlinico A. Gemelli, Roma, Italy. mzollino@rm.unicatt.it
Marcella
M
Zollino
Fiorella
F
Gurrieri
Daniela
D
Orteschi
Giuseppe
G
Marangi
Vincenzo
V
Leuzzi
Giovanni
G
Neri
D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology*; D002675:Child, Preschool; D002872:Chromosome Deletion; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004268:DNA-Binding Proteins / Q000235:genetics; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D007805:Language Development Disorders / Q000175:diagnosis / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D063146:Polycomb-Group Proteins; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics; D020703:ras GTPase-Activating Proteins / Q000235:genetics
C416667:CUTA protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C112309:PHF1 protein, human; D063146:Polycomb-Group Proteins; C484739:SYNGAP1 protein, human; D014157:Transcription Factors; D020703:ras GTPase-Activating Proteins