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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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Facial appearance of Patient 1 at the age of 13 years (A), Patient 2 at the age of 4 years (B), Patient 3 at the age of 6.5 years (C), and Patient 4 at the age of 5.5 years (D). All patients have distinct, similar dysmorphic facial features, including prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia.
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Figure 1: Facial appearance of Patient 1 at the age of 13 years (A), Patient 2 at the age of 4 years (B), Patient 3 at the age of 6.5 years (C), and Patient 4 at the age of 5.5 years (D). All patients have distinct, similar dysmorphic facial features, including prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia.

Mentions: Patient 1 (reported in DECIPHER database with identification # 256835) was a 15-year-old girl, the second child to non-consanguineous healthy Norwegian parents. Pregnancy and delivery were uneventful, with the following birth measures: weight 4470 g (97th centile), length 55 cm (>97th centile) and occipitofrontal circumference (OFC) 36 cm (75th centile). Global developmental delay was present from early childhood and she walked independently at 3.5 years of age. Testing with Reynell Developmental Language Scales and British Picture Vocabulary Scale at age 9 years, and Leiter International Performance Scale-Revised (Leiter-R) at age 9 and 10 years, indicated a mental age between 3 and 4 years, with expressive language below 3 years. The test results were consistent with moderate intellectual disability (IQ 35–49). A cerebral magnetic resonance imaging (MRI) examination at age 8 years showed unspecific periventricular white matter changes. She has had seizure-suspected syncope episodes from 13 years of age, but an electroencephalogram (EEG) was normal. At the last examination, at age 15 years, her weight was 53.7 kg (50th centile), height 157.5 cm (10th centile) and OFC 54 cm (25th centile). Her vocabulary consisted of 20–30 words, no sentences, and her articulation was blurred. She was hyperactive with a short concentration span, and had sleeping difficulties. She demonstrated unsteady and broad-based gait with difficulties standing on one leg at a time, and a remarkable inability to jump on one as well as on two legs (Additional file2: Video Patient 1). Dyspraxia was suggested by a discrepancy in performance between on-command and self-initiated tasks and language. Muscle tone was normal. Hearing and vision were normal. Ultrasound scan of kidneys was normal. She had pes planovalgus, short halluxes and apparently long 2nd toes bilaterally. X-ray images of hands and feet revealed shortening of the 1st and 3rd -5th metacarpal bones of the left hand and the 1st and 5th metacarpal bones of the right hand, and bilateral short 1st metatarsal bones (Additional file3: Figure S1). Dysmorphic facial features (Figure1A) and minor congenital anomalies in this patient are listed in Table1.


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)

Facial appearance of Patient 1 at the age of 13 years (A), Patient 2 at the age of 4 years (B), Patient 3 at the age of 6.5 years (C), and Patient 4 at the age of 5.5 years (D). All patients have distinct, similar dysmorphic facial features, including prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Facial appearance of Patient 1 at the age of 13 years (A), Patient 2 at the age of 4 years (B), Patient 3 at the age of 6.5 years (C), and Patient 4 at the age of 5.5 years (D). All patients have distinct, similar dysmorphic facial features, including prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia.
Mentions: Patient 1 (reported in DECIPHER database with identification # 256835) was a 15-year-old girl, the second child to non-consanguineous healthy Norwegian parents. Pregnancy and delivery were uneventful, with the following birth measures: weight 4470 g (97th centile), length 55 cm (>97th centile) and occipitofrontal circumference (OFC) 36 cm (75th centile). Global developmental delay was present from early childhood and she walked independently at 3.5 years of age. Testing with Reynell Developmental Language Scales and British Picture Vocabulary Scale at age 9 years, and Leiter International Performance Scale-Revised (Leiter-R) at age 9 and 10 years, indicated a mental age between 3 and 4 years, with expressive language below 3 years. The test results were consistent with moderate intellectual disability (IQ 35–49). A cerebral magnetic resonance imaging (MRI) examination at age 8 years showed unspecific periventricular white matter changes. She has had seizure-suspected syncope episodes from 13 years of age, but an electroencephalogram (EEG) was normal. At the last examination, at age 15 years, her weight was 53.7 kg (50th centile), height 157.5 cm (10th centile) and OFC 54 cm (25th centile). Her vocabulary consisted of 20–30 words, no sentences, and her articulation was blurred. She was hyperactive with a short concentration span, and had sleeping difficulties. She demonstrated unsteady and broad-based gait with difficulties standing on one leg at a time, and a remarkable inability to jump on one as well as on two legs (Additional file2: Video Patient 1). Dyspraxia was suggested by a discrepancy in performance between on-command and self-initiated tasks and language. Muscle tone was normal. Hearing and vision were normal. Ultrasound scan of kidneys was normal. She had pes planovalgus, short halluxes and apparently long 2nd toes bilaterally. X-ray images of hands and feet revealed shortening of the 1st and 3rd -5th metacarpal bones of the left hand and the 1st and 5th metacarpal bones of the right hand, and bilateral short 1st metatarsal bones (Additional file3: Figure S1). Dysmorphic facial features (Figure1A) and minor congenital anomalies in this patient are listed in Table1.

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