Phenotypes associated with this allele

• Allele Symbol: Chd7^{tm2a(EUCOMM)Wtsi}
• Allele Name: targeted mutation 2a, Wellcome Trust Sanger Institute
• Allele ID: MGI:4433295
• Summary: 8 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Chd7^tm2a(EUCOMM)Wtsi/Chd7^tm2a(EUCOMM)Wtsi	involves: 129S5/SvEvBrd * C57BL/6N	MGI:7492423
hm2	Chd7^tm2a(EUCOMM)Wtsi/Chd7^tm2a(EUCOMM)Wtsi	involves: 129S6/SvEvTac * C57BL/6N	MGI:5559524
ht3	Chd7^tm2a(EUCOMM)Wtsi/Chd7^+	129S5;B6N-Chd7^tm2a(EUCOMM)Wtsi/Wtsi	MGI:5781596
ht4	Chd7^tm2a(EUCOMM)Wtsi/Chd7^+	involves: 129S5/SvEvBrd * C57BL/6N	MGI:7492422
ht5	Chd7^tm2a(EUCOMM)Wtsi/Chd7^+	involves: 129S6/SvEvTac * C57BL/6N	MGI:5559523
cn6	Chd7^tm2a(EUCOMM)Wtsi/Chd7^tm2a(EUCOMM)Wtsi E2f1^Tg(Wnt1-cre)2Sor/E2f1^+ Gt(ROSA)26Sor^tm4(ACTB-tdTomato,-EGFP)Luo/Gt(ROSA)26Sor^+	involves: 129 * C3H * C57BL/6 * C57BL/6N	MGI:6490654
cn7	Chd7^tm2a(EUCOMM)Wtsi/Chd7^tm2a(EUCOMM)Wtsi Tg(Tek-cre)1Ywa/0	involves: C57BL/6 * C57BL/6J * C57BL/6N * SJL	MGI:7493911
cn8	Chd7^tm2a(EUCOMM)Wtsi/Chd7^tm2a(EUCOMM)Wtsi Mesp1^tm2(cre)Ysa/Mesp1^+	involves: C57BL/6J * C57BL/6N * C57BL/6NCrlj * CBA/JNCrlj	MGI:7377746

Genotype
MGI:7492423

hm1

• Allelic Composition: Chd7^{tm2a(EUCOMM)Wtsi}/Chd7^{tm2a(EUCOMM)Wtsi}
• Genetic Background: involves: 129S5/SvEvBrd * C57BL/6N

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

embryonic lethality during organogenesis, incomplete penetrance ( J:330596 )

• only 2 homozygous embryos were found at E14.5, suggesting most die mid-gestation

Genotype
MGI:5559524

hm2

• Allelic Composition: Chd7^{tm2a(EUCOMM)Wtsi}/Chd7^{tm2a(EUCOMM)Wtsi}
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6N

embryo

embryonic growth arrest ( J:207089 )

• no apparent gross abnormality at E9.5 but fully penetrant growth arrest at E10.5

mortality/aging

embryonic lethality during organogenesis, complete penetrance ( J:207089 )

• at E10.5

cellular

decreased fetal cardiomyocyte proliferation ( J:207089 )

• at E10.0

increased cardiomyocyte apoptosis ( J:207089 )

• at E10.0

abnormal epigenetic regulation of gene expression ( J:207089 )

• significantly reduced active epigenetic state of Nkx2-5 enhancers in E10.0 hearts

cardiovascular system

cardiovascular system phenotype ( J:207089 )

N • no myocardial defect at E9.5

thin myocardium ( J:207089 )

• at E10.5, mutant displays hypocellular myocardial wall

atrioventricular cushion hypoplasia ( J:207089 )

• fewer mesenchymal cells present in AV cushions at E9.5

• at E10.5, mutant displays hypocellular AV cushions

decreased fetal cardiomyocyte proliferation ( J:207089 )

• at E10.0

muscle

thin myocardium ( J:207089 )

• at E10.5, mutant displays hypocellular myocardial wall

decreased fetal cardiomyocyte proliferation ( J:207089 )

• at E10.0

increased cardiomyocyte apoptosis ( J:207089 )

• at E10.0

Genotype
MGI:5781596

ht3

• Allelic Composition: Chd7^{tm2a(EUCOMM)Wtsi}/Chd7⁺
• Genetic Background: 129S5;B6N-Chd7^{tm2a(EUCOMM)Wtsi}/Wtsi
• Cell Lines: EPD0019_1_D07

Data Sources

IMPC Data for Chd7

behavior/neurological

abnormal behavior ( J:175295 )

IMPC - WTSI

hyperactivity ( J:175295 )

IMPC - WTSI

skeleton

decreased lumbar vertebrae number ( J:175295 )

IMPC - WTSI

growth/size/body

decreased body weight ( J:165965 )

♂

IMPC - WTSI

decreased body length ( J:165965 )

IMPC - WTSI

Genotype
MGI:7492422

ht4

• Allelic Composition: Chd7^{tm2a(EUCOMM)Wtsi}/Chd7⁺
• Genetic Background: involves: 129S5/SvEvBrd * C57BL/6N

nervous system

abnormal corpus callosum morphology ( J:330596 )

• absence of midline crossing resulting in dysgenesis of the corpus callosum in 3 of 3 mice

decreased brain internal capsule size ( J:330596 )

• 32% decrease in size

increased habenula size ( J:330596 )

• 41% increase in size

abnormal retrosplenial granular cortex morphology ( J:330596 )

• abnormally shaped

abnormal hippocampus morphology ( J:330596 )

• abnormally shaped

increased mammillothalamic tract size ( J:330596 )

• increase of 100% on average on both sides of the brain

behavior/neurological

behavior/neurological phenotype ( J:330596 )

N • no increase in locomotor activity during a modified SHIRPA or in the open field unlike mice heterozygous for Chd7^Whi

N • no change in heat sensitivity compared to controls

abnormal response to stress-induced hyperthermia ( J:330596 )

• show a trend toward reduced response

decreased grip strength ( J:330596 )

• less severe than in mice heterozygous for Chd7^Whi

hematopoietic system

decreased hematocrit ( J:330596 )

decreased hemoglobin content ( J:330596 )

decreased red blood cell distribution width ( J:330596 )

increased NK T cell number ( J:330596 )

decreased leukocyte cell number ( J:330596 )

decreased monocyte cell number ( J:330596 )

• percentage tends to be decreased but is not statistically significant

vision/eye

abnormal pupil morphology ( J:330596 )

• abnormal pupil position or shape in 5 of 14 mice

cataract ( J:330596 )

• opaque lenses in mice with normal pupils only

homeostasis/metabolism

abnormal response to stress-induced hyperthermia ( J:330596 )

• show a trend toward reduced response

increased blood uric acid level ( J:330596 )

abnormal circulating lipoprotein level ( J:330596 )

• decreased LDL levels

abnormal circulating enzyme level ( J:330596 )

decreased circulating alanine transaminase level ( J:330596 )

increased circulating alkaline phosphatase level ( J:330596 )

decreased circulating total protein level ( J:330596 )

growth/size/body

decreased lean body mass ( J:330596 )

• decreased by 16%

decreased body weight ( J:330596 )

• decreased weight from early life to adulthood

decreased body length ( J:330596 )

• at 14 weeks of age

skeleton

decreased bone mineral content ( J:330596 )

• marginally reduced (15%)

immune system

increased NK T cell number ( J:330596 )

decreased leukocyte cell number ( J:330596 )

decreased monocyte cell number ( J:330596 )

• percentage tends to be decreased but is not statistically significant

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
CHARGE syndrome		DOID:0050834	OMIM:214800	J:330596

Genotype
MGI:5559523

ht5

• Allelic Composition: Chd7^{tm2a(EUCOMM)Wtsi}/Chd7⁺
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6N

behavior/neurological

head bobbing ( J:207089 )

circling ( J:207089 )

Genotype
MGI:6490654

cn6

• Allelic Composition: Chd7^{tm2a(EUCOMM)Wtsi}/Chd7^{tm2a(EUCOMM)Wtsi}; E2f1^{Tg(Wnt1-cre)2Sor}/E2f1⁺; Gt(ROSA)26Sor^{tm4(ACTB-tdTomato,-EGFP)Luo}/Gt(ROSA)26Sor⁺
• Genetic Background: involves: 129 * C3H * C57BL/6 * C57BL/6N

mortality/aging

perinatal lethality, complete penetrance ( J:298597 )

cardiovascular system

pulmonary trunk hypoplasia ( J:298597 )

• about 5% of mutants show a hypoplastic pulmonary trunk at E15.5 and E16.5

interrupted aortic arch, type b ( J:298597 )

• about 30% of mutants exhibit interrupted aortic arch, type b at E15.5 and E16.5

abnormal conotruncal ridge morphology ( J:298597 )

• the number of neural crest cells in the proximal outflow tract cushions is reduced at E11.5

double outlet right ventricle ( J:298597 )

• all mutants exhibit the double outlet right ventricle at E15.5 and E16.5

ventricular septal defect ( J:298597 )

• all mutants exhibit a ventricular septal defect at E15.5 and E16.5

craniofacial

small frontal bone ( J:298597 )

• E17.5 mutants show a smaller frontal bone

small mandible ( J:298597 )

• E17.5 mutants exhibit a smaller mandible

small maxilla ( J:298597 )

• E17.5 mutants exhibit a smaller maxilla

abnormal pharyngeal arch morphology ( J:298597 )

• 30% of mutants show increased cell death in the pharyngeal arch region

• however, no reduction in cell proliferation is seen in the pharyngeal arch regions at E11.5

embryo

abnormal pharyngeal arch morphology ( J:298597 )

• 30% of mutants show increased cell death in the pharyngeal arch region

• however, no reduction in cell proliferation is seen in the pharyngeal arch regions at E11.5

impaired cranial neural crest cell differentiation ( J:298597 )

• marker analysis at E11.5 indicates that differentiation of cranial neural crest cells into smooth muscle cells is reduced

abnormal embryonic tissue physiology ( J:298597 )

• cell proliferation in the neural crest cell derivatives, aorta and pulmonary trunk walls, is reduced at E12.5

• 30% of mutants show increased cell death in the pharyngeal arch region

• however, no reduction in cell proliferation is seen in the dorsal neural tube, pharyngeal arch regions and outflow tract cushions at E11.5 and no increase in cell death is seen in the dorsal neural tube and outflow tract cushions at E11.5

abnormal cranial neural crest cell migration ( J:298597 )

• the number of neural crest cells in the proximal outflow tract cushions is reduced at E11.5 however, no increase in cell death or reduction in cell proliferation is seen in the outflow tract cushions, indicating that cranial neural crest cell migration to outflow tract cushions is reduced

nervous system

impaired cranial neural crest cell differentiation ( J:298597 )

• marker analysis at E11.5 indicates that differentiation of cranial neural crest cells into smooth muscle cells is reduced

skeleton

small frontal bone ( J:298597 )

• E17.5 mutants show a smaller frontal bone

small mandible ( J:298597 )

• E17.5 mutants exhibit a smaller mandible

small maxilla ( J:298597 )

• E17.5 mutants exhibit a smaller maxilla

cellular

abnormal cranial neural crest cell migration ( J:298597 )

• the number of neural crest cells in the proximal outflow tract cushions is reduced at E11.5 however, no increase in cell death or reduction in cell proliferation is seen in the outflow tract cushions, indicating that cranial neural crest cell migration to outflow tract cushions is reduced

Genotype
MGI:7493911

cn7

• Allelic Composition: Chd7^{tm2a(EUCOMM)Wtsi}/Chd7^{tm2a(EUCOMM)Wtsi}; Tg(Tek-cre)1Ywa/0
• Genetic Background: involves: C57BL/6 * C57BL/6J * C57BL/6N * SJL

mortality/aging

preweaning lethality, incomplete penetrance ( J:225736 )

• number of live pups recorded at P10 is 5 versus expected 8 (based on Mendelian ratios)

cardiovascular system

cardiovascular system phenotype ( J:225736 )

N • no embryos exhibit hemorrhaging at E15.5

N • no double outlet right ventricle (DORV) or common arterial trunk (CAT) are observed at E15.5, suggesting normal arterial pole septation

N • no double inlet left ventricle (DILV) or venous valve defects are observed

N • coronary vein development is normal

interrupted aortic arch, type b ( J:225736 )

• at E15.5, 12.5% of embryos show interrupted aortic arch type B (IAA-B)

abnormal myocardium compact layer morphology ( J:225736 )

• at E15.5, 37.5% of embryos show myocardial non-compaction

atrial septal defect ( J:225736 )

• at E15.5, 12.5% of embryos show an atrial septal defect (ASD) only

atrioventricular septal defect ( J:225736 )

• at E15.5, 12.5% of embryos exhibit an atrioventricular septal defect (AVSD)

ventricular septal defect ( J:225736 )

• at E15.5, 25% of embryos show a ventricular septal defect (VSD) only

homeostasis/metabolism

edema ( J:225736 )

• at E15.5, 18% of embryos display severe edema

muscle

abnormal myocardium compact layer morphology ( J:225736 )

• at E15.5, 37.5% of embryos show myocardial non-compaction

Genotype
MGI:7377746

cn8

• Allelic Composition: Chd7^{tm2a(EUCOMM)Wtsi}/Chd7^{tm2a(EUCOMM)Wtsi}; Mesp1^tm2(cre)Ysa/Mesp1⁺
• Genetic Background: involves: C57BL/6J * C57BL/6N * C57BL/6NCrlj * CBA/JNCrlj

mortality/aging

perinatal lethality, complete penetrance ( J:225736 )

• no live pups are born or recorded at P10

lethality throughout fetal growth and development, incomplete penetrance ( J:225736 )

• only ~75% of embryos survive to E15.5, with no necrotic embryos detected up to E13.5; the number of embryos collected at E18.5 is significantly below the expected Mendelian ratios (2 versus expected 9)

cardiovascular system

cardiovascular system phenotype ( J:225736 )

N • at E10.5, all embryos exhibit normal pharyngeal arch artery (PAA) development

interrupted aortic arch, type b ( J:225736 )

• at E15.5, 21% (3 of 14) of embryos show interrupted aortic arch type B (IAA-B)

• IAA-Bs seen at E15.5 are likely due to a PAA remodeling defect

abnormal vein morphology ( J:225736 )

• at E15.5, 90% (9 of 10) embryos show absent or poorly formed venous valves

abnormal coronary vein morphology ( J:225736 )

• at E15.5, coronary veins show either severe truncation of the vessels or ectopic formation of multiple small veins

abnormal myocardial trabeculae morphology ( J:225736 )

• at E15.5, the % of overall thickness of the trabecular layer in the left ventricle is 65% versus 49% in control hearts

abnormal myocardium compact layer morphology ( J:225736 )

• at E15.5, 80% of embryos show myocardial non-compaction

• however, development of the epicardium appears normal at E13.5

thin ventricle myocardium compact layer ( J:225736 )

• at E15.5, the compact myocardial layer of the ventricular wall is thin, esp. in the left ventricle

abnormal cardiac outflow tract development ( J:225736 )

• undifferentiated second heart field (SHF) progenitors are normally added to the arterial pole at E11.5, indicating that outflow tract defects are likely due to subsequent differentiation of SHF-derived cells

abnormal truncus arteriosus septation ( J:225736 )

• at E13.5, one of 10 embryos shows a common arterial trunk (CAT) where the outflow tract is not fully septated into a separate aorta and pulmonary trunk

aortopulmonary window ( J:225736 )

• at E13.5, one of 10 embryos shows an aortopulmonary window above a common set of valves

abnormal heart development ( J:225736 )

• hearts exhibit major septation defects affecting both the arterial and venous poles; great vessel, OFT and septation defects are observed

• at E11.5, the vestibular spine is absent or reduced in size

• at E15.0, cardiac innervation is defective with significantly fewer axonal branch points seen on the dorsal surface of the heart; the % of the dorsal ventricular surface area covered by extending axons is reduced to 27% versus 57% in control hearts

abnormal atrioventricular cushion morphology ( J:225736 )

• at E11.5, the endocardial cushions are abnormally positioned (rotated) within the AV canal

• however, no hypocellular AV cushion defect is noted at t E10.5 or E11.5, indicating that mesenchymal population of the cushions is not affected

double outlet right ventricle ( J:225736 )

• at E15.5, 60% (6 of 10) of hearts show double outlet arising from the right ventricle (DORV)

common atrioventricular valve ( J:225736 )

• at E15.5, all (10 of 10) hearts show a common atrioventricular (AV) valve

double inlet heart left ventricle ( J:225736 )

• at E15.5, all (10 of 10) hearts show double inlet left ventricle (DILV) including interventricular communication and common atrioventricular (AV) valves

atrioventricular septal defect ( J:225736 )

• at E15.5, all (10 of 10) hearts exhibit an atrioventricular septal defect

thin ventricular wall ( J:225736 )

• overall thickness of both the right and left ventricles is significantly reduced

hemorrhage ( J:225736 )

• at E15.5, 64% of embryos display hemorrhaging

abnormal fetal cardiomyocyte physiology ( J:225736 )

• ex vivo, only 39% of E13.5 cardiomyocytes respond to electrical pacing with regular Ca²⁺ transients recorded at the expected 1 s intervals versus 95% of control cells, indicating impaired excitation-contraction coupling

congestive heart failure ( J:225736 )

• at E15.5, over 90% of embryos show severe edema and/or hemorrhaging, indicative of cardiac failure

homeostasis/metabolism

edema ( J:225736 )

• at E15.5, 68% of embryos display severe edema

nervous system

abnormal innervation ( J:225736 )

• at E15.0, cardiac innervation is defective with significantly fewer axonal branch points seen on the dorsal surface of the heart; the % of the dorsal ventricular surface area covered by extending axons is reduced to a 27% versus 57% in control hearts

muscle

abnormal myocardial trabeculae morphology ( J:225736 )

• at E15.5, the % of overall thickness of the trabecular layer in the left ventricle is 65% versus 49% in control hearts

abnormal myocardium compact layer morphology ( J:225736 )

• at E15.5, 80% of embryos show myocardial non-compaction

• however, development of the epicardium appears normal at E13.5

thin ventricle myocardium compact layer ( J:225736 )

• at E15.5, the compact myocardial layer of the ventricular wall is thin, esp. in the left ventricle