Abstract
BackgroundChromosome 17q21.31 microdeletion syndrome is a multisystem genomic disorder caused by a recurrent 600-kb-long deletion, or haploinsufficiency of the chromatin modifier gene KANSL1, which maps to that region. Patients with KANSL1 intragenic mutations have been reported to display the major clinical features of 17q21.31 microdeletion syndrome. However, they did not exhibit the full clinical spectrum of this disorder, which might indicate that an additional gene or genes, located in the 17q21.31 locus, might also be involved in the syndrome’s phenotype.MethodsConventional and molecular karyotypes were performed on a female patient with intellectual disability, agenesis of the corpus callosum, heart defects, hydronephrosis, hypotonia, pigmentary skin anomalies and facial dysmorphic features. FISH analysis was conducted for chromosomal breakpoint localization. qRT-PCR was applied for the comparative gene expression of KANSL1 gene in the patient and a control group.ResultsHerein, we present the first report of disruption and haploinsufficiency of the KANSL1 gene, secondary to a t(1;17)(q12;q21)dn chromosomal translocation in a girl that also carried a de novo ~289-kb deletion on 16p11.2. KANSL1 gene expression studies and comparative clinical analysis of patients with 17q21.31 deletions and intragenic KANSL1 gene defects indicate that KANSL1 dysfunction is associated with the full spectrum of the 17q21.31 microdeletion syndrome, which includes characteristic facial features, hypotonia, intellectual disability, and structural defects of the brain, heart and genitourinary system, as well as, musculoskeletal and neuroectodermal anomalies. Moreover, we provide further evidence for the overlapping clinical phenotype of this condition with the cardio-facio-cutaneous (CFC) syndrome.ConclusionsKANSL1 gene haploinsufficiency is necessary and sufficient to cause the full spectrum of the 17q21.31 microdeletion syndrome. We hypothesize that the KANSL1 gene might have an effect on the Ras/mitogen-activated protein kinase (MAPK) pathway activity, which is known to be deregulated in the CFC syndrome. This pathway has a crucial role in the development of the heart and craniofacial morphology, as well as the skin, eye, brain and musculoskeletal systems.
Highlights
Chromosome 17q21.31 microdeletion syndrome is a multisystem genomic disorder caused by a recurrent 600-kb-long deletion, or haploinsufficiency of the chromatin modifier gene KANSL1, which maps to that region
Additional studies with flanking probes RP11-368D10 and RP11-259G18 showed one signal on der(17) and one on der(1) chromosomes, respectively. These results indicated that RP11-782E01 and RP1186C01 Bacterial artificial chromosome (BAC) probes spanned the translocation breakpoint, placing the breakpoint within a 65.6-kb region of overlap at the 17q21.31 band, which would disrupt the KANSL1 gene (Fig. 3)
We present the first report of haploinsufficiency of the KANSL1 gene caused by gene interruption, secondary to a de novo (1;17)(q12;q21) chromosomal translocation
Summary
Chromosome 17q21.31 microdeletion syndrome is a multisystem genomic disorder caused by a recurrent 600-kb-long deletion, or haploinsufficiency of the chromatin modifier gene KANSL1, which maps to that region. Patients with KANSL1 intragenic mutations have been reported to display the major clinical features of 17q21.31 microdeletion syndrome. They did not exhibit the full clinical spectrum of this disorder, which might indicate that an additional gene or genes, located in the 17q21.31 locus, might be involved in the syndrome’s phenotype. Recent reports of small atypical deletions and heterozygous intragenic mutations in KANSL1 demonstrated that haploinsufficiency of this gene is responsible for the major clinical signs of the syndrome [8, 9]. With the exception of a ventricular septal defect that spontaneously corrected, structural defects were not present in patients with intragenic KANSL1 mutations. It is plausible that additional genes at the 17q21.31 locus might account for the severity of the clinical phenotype of the del17q21.31 syndrome
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