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.

The 22q11.2 deletion syndrome is typically caused by haploinsufficiency of a 3 Mb region that extends from LCR22-A until LCR22-D, while the recurrent recombination between any of the LCR22-D to H causes the 22q11.2 distal deletion syndrome. Here, we describe three patients with a de novo atypical ∼1.4 Mb 22q11.2 deletion that involves LCR22-C to a region beyond D (LCR22-C to D/E), encompassing the distal portion of the typical deleted region and the proximal portion of the distal deletion. We also review six previous published patients with the same rearrangement and compare their features with those found in patients with overlapping deletions. Patients with LCR22-C to D/E deletion present a recognizable phenotype characterized by facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay. Genotype-phenotype analysis of the patients indicates that CRKL and MAPK1 genes play an important role as causative factors for the main clinical features of the syndrome. In particular, CRKL gene seems to be involved in the occurrence of conotruncal cardiac anomalies, mainly tetralogy of Fallot. © 2016 Wiley Periodicals, Inc.