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

Barøy T, Misceo D, Strømme P, Stray-Pedersen A, Holmgren A, Rødningen OK, Blomhoff A, Helle JR, Stormyr A, Tvedt B, Fannemel M, Frengen E - Orphanet J Rare Dis (2013)

Bottom Line: 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.Due to the characteristic facial appearance, JARID2 haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Genetics, University of Oslo, P,O, Box 1036, Blindern, Oslo N-0315, Norway.

ABSTRACT

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.

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Localization of the deletions in chromosome 6p22.3-p24.1 in our five patients (top) and the overlapping part of the deletions in 17 out of 19 previously reported patients. SRO I in Patients 1-4 from the present report is 189 kb (red box), and SRO II in Patients 1-3 and 5 is 116 kb (green box). JARID2 and ATXN1 are deleted in 14 and 16 patients, respectively. Patient codes and deletion coordinates for previous patients are according to[1], except M from[2]. CNVs recorded in the Database of Genomic Variants (projects.tcag.ca/variation) (below) are covering only a minor part of the region deleted in the five patients. For the two genes located within the SRO I, a single CNV in JARID2 was located in an intronic sequence, and two CNVs were reported in DTNBP1: one located in an intronic sequence and one copy number gain including the 5’UTR and the first exon. For the two genes located within SRO II, no CNVs were reported in GMPR and one CNV, a gain in an intronic sequence observed in three individuals, was recorded in ATXN1. Data were uploaded into UCSC Genome Browser (http://genome.ucsc.edu).
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Figure 3: Localization of the deletions in chromosome 6p22.3-p24.1 in our five patients (top) and the overlapping part of the deletions in 17 out of 19 previously reported patients. SRO I in Patients 1-4 from the present report is 189 kb (red box), and SRO II in Patients 1-3 and 5 is 116 kb (green box). JARID2 and ATXN1 are deleted in 14 and 16 patients, respectively. Patient codes and deletion coordinates for previous patients are according to[1], except M from[2]. CNVs recorded in the Database of Genomic Variants (projects.tcag.ca/variation) (below) are covering only a minor part of the region deleted in the five patients. For the two genes located within the SRO I, a single CNV in JARID2 was located in an intronic sequence, and two CNVs were reported in DTNBP1: one located in an intronic sequence and one copy number gain including the 5’UTR and the first exon. For the two genes located within SRO II, no CNVs were reported in GMPR and one CNV, a gain in an intronic sequence observed in three individuals, was recorded in ATXN1. Data were uploaded into UCSC Genome Browser (http://genome.ucsc.edu).

Mentions: Karyotype analysis of all five patients was normal. Deletions in chromosome 6p22.3-p24.1 of 116 kb to 4.8 Mb in size were detected by aCGH analysis in the five patients (Table1 and Figure2 and3). Patients 4 and 5 carried non-overlapping deletions that were both included in the deletions of Patients 1–3. Patient 1 had a deletion involving 6p22.3-p24.1 of 4.8-4.9 Mb and Patient 2 had a 3.1 Mb deletion overlapping the proximal 2.8 Mb of the deletion in Patient 1. Array analysis in Patient 3 revealed a 2.3-2.6 Mb deletion included in the region deleted in Patients 1 and 2, and the common region deleted in these three patients contained six genes: JARID2, DTNBP1, MYLIP, MIR4639, GMPR and ATXN1. In Patient 4, we identified a 189–241 kb deletion, including part of the genes JARID2 and DTNBP1, which was the region defining SRO I, deleted in Patients 1–4. A 116–163 kb deletion was detected in Patient 5 including the gene GMPR and part of the gene ATXN1. This was the region defining SRO II, deleted in Patients 1–3 and 5. The partial deletion of JARID2 and DTNBP1 in Patient 4, and ATXN1 in Patient 5 removed the 3’end of the genes, deleting exons 3–18 in JARID2, exons 7–10 in DTNBP1 and exons 8–9 in ATXN1 and the 3’ untranslated region (UTR) in all cases. Only copy number variants (CNVs) covering minor parts of the region deleted in our patients were recorded in the Database of Genomic Variants (DGV, projects.tcag.ca/variation, accessed in November 2012) (Figure3). From the aCGH result it was uncertain if the gene KDM1B was deleted in Patient 2, as it was partly included in the region between the last deleted and the first normal aCGH oligo at the proximal border, and it was shown by qPCR not to be deleted. No additional genes were located in the region between the minimal and maximal sizes of the deletions, and the breakpoints of the deletions given by the aCGH results were therefore not investigated further. All five chromosome 6 deletions were verified, by qPCR (Patients 1–4) or by performing a second aCGH with higher resolution (Patient 5), and were found to be de novo by aCGH analysis of the parental samples. In addition, the aCGH analysis detected a 463 kb duplication of chromosome 4q23 in Patient 3 (chr4:100124832–100588141, bp) and a 94 kb deletion of chromosome 11p13 in Patient 5 (chr11: 32697424–32791452, bp). Two DECIPHER patients (identification # 250971 and # 256563) were reported with a duplication that overlaps the duplicated region in Patient 3. However, both duplications were larger (both about 3.6 Mb), and one of the individuals also had two other aberrations. Similarly, one DECIPHER patient (identification # 253354) had a deletion covering the region deleted in Patient 5, which also was larger (4.1 Mb). A minor part of the duplication of chromosome 4q23, and most of the deletion of chromosome 11p13 overlapped with CNVs in DGV. These aberrations in Patient 3 and 5 were inherited from healthy parents and the gene content did not appear relevant for the clinical presentation of the patients.


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

Barøy T, Misceo D, Strømme P, Stray-Pedersen A, Holmgren A, Rødningen OK, Blomhoff A, Helle JR, Stormyr A, Tvedt B, Fannemel M, Frengen E - Orphanet J Rare Dis (2013)

Localization of the deletions in chromosome 6p22.3-p24.1 in our five patients (top) and the overlapping part of the deletions in 17 out of 19 previously reported patients. SRO I in Patients 1-4 from the present report is 189 kb (red box), and SRO II in Patients 1-3 and 5 is 116 kb (green box). JARID2 and ATXN1 are deleted in 14 and 16 patients, respectively. Patient codes and deletion coordinates for previous patients are according to[1], except M from[2]. CNVs recorded in the Database of Genomic Variants (projects.tcag.ca/variation) (below) are covering only a minor part of the region deleted in the five patients. For the two genes located within the SRO I, a single CNV in JARID2 was located in an intronic sequence, and two CNVs were reported in DTNBP1: one located in an intronic sequence and one copy number gain including the 5’UTR and the first exon. For the two genes located within SRO II, no CNVs were reported in GMPR and one CNV, a gain in an intronic sequence observed in three individuals, was recorded in ATXN1. Data were uploaded into UCSC Genome Browser (http://genome.ucsc.edu).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3675438&req=5

Figure 3: Localization of the deletions in chromosome 6p22.3-p24.1 in our five patients (top) and the overlapping part of the deletions in 17 out of 19 previously reported patients. SRO I in Patients 1-4 from the present report is 189 kb (red box), and SRO II in Patients 1-3 and 5 is 116 kb (green box). JARID2 and ATXN1 are deleted in 14 and 16 patients, respectively. Patient codes and deletion coordinates for previous patients are according to[1], except M from[2]. CNVs recorded in the Database of Genomic Variants (projects.tcag.ca/variation) (below) are covering only a minor part of the region deleted in the five patients. For the two genes located within the SRO I, a single CNV in JARID2 was located in an intronic sequence, and two CNVs were reported in DTNBP1: one located in an intronic sequence and one copy number gain including the 5’UTR and the first exon. For the two genes located within SRO II, no CNVs were reported in GMPR and one CNV, a gain in an intronic sequence observed in three individuals, was recorded in ATXN1. Data were uploaded into UCSC Genome Browser (http://genome.ucsc.edu).
Mentions: Karyotype analysis of all five patients was normal. Deletions in chromosome 6p22.3-p24.1 of 116 kb to 4.8 Mb in size were detected by aCGH analysis in the five patients (Table1 and Figure2 and3). Patients 4 and 5 carried non-overlapping deletions that were both included in the deletions of Patients 1–3. Patient 1 had a deletion involving 6p22.3-p24.1 of 4.8-4.9 Mb and Patient 2 had a 3.1 Mb deletion overlapping the proximal 2.8 Mb of the deletion in Patient 1. Array analysis in Patient 3 revealed a 2.3-2.6 Mb deletion included in the region deleted in Patients 1 and 2, and the common region deleted in these three patients contained six genes: JARID2, DTNBP1, MYLIP, MIR4639, GMPR and ATXN1. In Patient 4, we identified a 189–241 kb deletion, including part of the genes JARID2 and DTNBP1, which was the region defining SRO I, deleted in Patients 1–4. A 116–163 kb deletion was detected in Patient 5 including the gene GMPR and part of the gene ATXN1. This was the region defining SRO II, deleted in Patients 1–3 and 5. The partial deletion of JARID2 and DTNBP1 in Patient 4, and ATXN1 in Patient 5 removed the 3’end of the genes, deleting exons 3–18 in JARID2, exons 7–10 in DTNBP1 and exons 8–9 in ATXN1 and the 3’ untranslated region (UTR) in all cases. Only copy number variants (CNVs) covering minor parts of the region deleted in our patients were recorded in the Database of Genomic Variants (DGV, projects.tcag.ca/variation, accessed in November 2012) (Figure3). From the aCGH result it was uncertain if the gene KDM1B was deleted in Patient 2, as it was partly included in the region between the last deleted and the first normal aCGH oligo at the proximal border, and it was shown by qPCR not to be deleted. No additional genes were located in the region between the minimal and maximal sizes of the deletions, and the breakpoints of the deletions given by the aCGH results were therefore not investigated further. All five chromosome 6 deletions were verified, by qPCR (Patients 1–4) or by performing a second aCGH with higher resolution (Patient 5), and were found to be de novo by aCGH analysis of the parental samples. In addition, the aCGH analysis detected a 463 kb duplication of chromosome 4q23 in Patient 3 (chr4:100124832–100588141, bp) and a 94 kb deletion of chromosome 11p13 in Patient 5 (chr11: 32697424–32791452, bp). Two DECIPHER patients (identification # 250971 and # 256563) were reported with a duplication that overlaps the duplicated region in Patient 3. However, both duplications were larger (both about 3.6 Mb), and one of the individuals also had two other aberrations. Similarly, one DECIPHER patient (identification # 253354) had a deletion covering the region deleted in Patient 5, which also was larger (4.1 Mb). A minor part of the duplication of chromosome 4q23, and most of the deletion of chromosome 11p13 overlapped with CNVs in DGV. These aberrations in Patient 3 and 5 were inherited from healthy parents and the gene content did not appear relevant for the clinical presentation of the patients.

Bottom Line: 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.Due to the characteristic facial appearance, JARID2 haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Genetics, University of Oslo, P,O, Box 1036, Blindern, Oslo N-0315, Norway.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus