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Background  Nineteen patients with deletions in chromosome 6p22-p24 have been published so far. The syndromic phenotype is varied, and includes intellectual disability, behavioural abnormalities, dysmorphic features and structural organ defects. Heterogeneous deletion breakpoints and sizes (1–17 Mb) and overlapping phenotypes have made the identification of the disease causing genes challenging. We suggest  JARID2  and  ATXN1,  both harbored in 6p22.3, as disease causing genes.    Methods and results  We describe five unrelated patients with  de novo  deletions (0.1-4.8 Mb in size) in chromosome 6p22.3-p24.1 detected by aCGH in a cohort of approximately 3600 patients ascertained for neurodevelopmental disorders. Two patients (Patients 4 and 5) carried non-overlapping deletions that were encompassed by the deletions of the remaining three patients (Patients 1–3), indicating the existence of two distinct dosage sensitive genes responsible for impaired cognitive function in 6p22.3 deletion-patients. The smallest region of overlap (SRO I) in Patients 1–4 (189 kb) included the genes  JARID2  and  DTNBP1 , while SRO II in Patients 1–3 and 5 (116 kb) contained  GMPR  and  ATXN1.  Patients with deletion of SRO I manifested variable degrees of cognitive impairment, gait disturbance and distinct, similar facial dysmorphic features (prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia) that might be ascribed to the haploinsufficiency of  JARID2.  Patients with deletion of SRO II showed intellectual disability and behavioural abnormalities, likely to be caused by the deletion of  ATXN1 . Patients 1–3 presented with lower cognitive function than Patients 4 and 5, possibly due to the concomitant haploinsufficiency of both  ATXN1  and  JARID2 . The chromatin modifier genes  ATXN1  and  JARID2  are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients. Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes.    Conclusions  Patients carrying  JARID2  deletion manifested with cognitive impairment, gait disturbance and a characteristic facial appearance, whereas patients with deletion of  ATXN1  seemed to be characterized by intellectual disability and behavioural abnormalities. Due to the characteristic facial appearance,  JARID2  haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.

Haploinsufficiency of two histone modifier genes on 6p22.3, ATXN1 and JARID2, is associated with intellectual disability