遗传性心脏疾病的基因诊断与遗传咨询
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• Autosomal dominant • Majority of cases
sporadic (De Novo)
• Microdeletion: 7q11.23
• ELN（弹力蛋白基因）: 血
管发育不良、特殊面容、 声音嘶哑等
(ELN point mutation: SVAS
only)
• LMK1: 认知缺陷 • GTF21：特殊面容
– 骨骼肌肉疾病 (9%) – 中枢神经系统疾病 (8%) – 尿路 或肾脏 (5%) – 消化道 (4%) – 腭裂 (1.8%)
CHD: 再发风险（recurrence risk）
• Isolated(单纯性) CHD: – Risk of second affected child 1-6%
CHD and Genetic
• Isolated (65-70%) – Multifactorial inheritance
• Component of syndrome (25-30%) – Single gene , Copy Number Variants or chromosomal
Aneuploidy(非整倍体) syndromes
Abnormal chromosomal structural syndromes
22q11 Deletion Syndrome
(DiGeorge, Shprintzen, velocardiofacial, Asymmetric crying facies
syndromes)
• 1/2000-4000 Live births • CHD (80~100%) • Facial Features (小颌畸形) • Endocrine Features (甲状旁腺发
Hቤተ መጻሕፍቲ ባይዱXA3 and TBX1
Williams Syndrome
• 1/7,500 live births • Distinctive facies
宽前额，双颞狭小，眶周丰满，短鼻子 颧骨发育不全、人中长，厚嘴唇，大嘴巴，小下巴， 突出的耳垂，星状/花边的虹膜
“小精灵样”脸谱
Williams Syndrome
或离子通道病 (Channelopathies) 其他：肺动脉高压(Pulmonary arterial hypertension)、
马凡氏综合征 ……
第一部分：先天性心脏病
(Congenital Heart Defects,CHD)
Congenital Heart Defects (CHD)： Epidemiology
– 50% recurrence risk • Autosomal recessive syndrome:
– 25% recurrence risk
Non-syndromic CHD: 再发风险（recurrence risk）
World J Cardiol. 2016 Feb 26;8(2):180-91.
• Parent with isolated CHD: – Risk of affected child up to 12% (higher if mother vs.
father with CHD) • Recurrence risk doubles if two first degree relatives • Autosomal dominant syndrome:
上海交通大学医学院附属
遗传性心脏疾病的基因 诊断与遗传咨询
遗传性心脏疾病
先天性心脏病 (Congenital Heart Defects,CHD) 遗传性心肌病 (Inherited Cardiomyopathy) 遗传性心律失常 (Inherited arrhythmia disorders)
• 8-10/1,000 births • CHD account for:
– 25% of all congenital malformations – 15% of all infant deaths
• 20% with one CHD will have a second • 25% will have a second malformation
Down Syndrome
• Phenotype:
-宽脸,平剖面,
-短鼻,眼距宽,大舌 -通贯手 -智力落后 • Cardiovascular(~50%)
-Complete AV -Canal -Primum ASD
(often with cleft MV) -VSD -PDA -TOF -DORV
• Week 5-Term: development of the conduction(传导) system
(Days 20-50: the most sensitive time for disturbances in formation of the CV system)
Most CHD multifactorial : Genetic and Environmental
育不全)
• Immune defect (胸腺缺如、甲状
旁腺发育不全)
• Genetics
-Autosomal Dominant -94% Sporadic -95% 22q11 microdeletion -Deletion either 3 Mb long (85%) or 1.5 Mb -Genes thought to be important:
Heart Development
• Week 3: CV System begins to develop
(Days 21-22: Cardiac contractions 收缩 begin)
• Week 3-8: Formation of the heart and major vessels(血管)
Single gene mutation syndromes
Alagille Syndrome
• Cardiovascular Disease: 90-97% • Hepatic Disease • Facial Features: 突出的额头，深陷的眼睛，下巴尖 • 搔痒、生长停滞、“白陶土样”大便 • Autosomal dominant • JAG1 gene, 20p12
sporadic (De Novo)
• Microdeletion: 7q11.23
• ELN（弹力蛋白基因）: 血
管发育不良、特殊面容、 声音嘶哑等
(ELN point mutation: SVAS
only)
• LMK1: 认知缺陷 • GTF21：特殊面容
– 骨骼肌肉疾病 (9%) – 中枢神经系统疾病 (8%) – 尿路 或肾脏 (5%) – 消化道 (4%) – 腭裂 (1.8%)
CHD: 再发风险（recurrence risk）
• Isolated(单纯性) CHD: – Risk of second affected child 1-6%
CHD and Genetic
• Isolated (65-70%) – Multifactorial inheritance
• Component of syndrome (25-30%) – Single gene , Copy Number Variants or chromosomal
Aneuploidy(非整倍体) syndromes
Abnormal chromosomal structural syndromes
22q11 Deletion Syndrome
(DiGeorge, Shprintzen, velocardiofacial, Asymmetric crying facies
syndromes)
• 1/2000-4000 Live births • CHD (80~100%) • Facial Features (小颌畸形) • Endocrine Features (甲状旁腺发
Hቤተ መጻሕፍቲ ባይዱXA3 and TBX1
Williams Syndrome
• 1/7,500 live births • Distinctive facies
宽前额，双颞狭小，眶周丰满，短鼻子 颧骨发育不全、人中长，厚嘴唇，大嘴巴，小下巴， 突出的耳垂，星状/花边的虹膜
“小精灵样”脸谱
Williams Syndrome
或离子通道病 (Channelopathies) 其他：肺动脉高压(Pulmonary arterial hypertension)、
马凡氏综合征 ……
第一部分：先天性心脏病
(Congenital Heart Defects,CHD)
Congenital Heart Defects (CHD)： Epidemiology
– 50% recurrence risk • Autosomal recessive syndrome:
– 25% recurrence risk
Non-syndromic CHD: 再发风险（recurrence risk）
World J Cardiol. 2016 Feb 26;8(2):180-91.
• Parent with isolated CHD: – Risk of affected child up to 12% (higher if mother vs.
father with CHD) • Recurrence risk doubles if two first degree relatives • Autosomal dominant syndrome:
上海交通大学医学院附属
遗传性心脏疾病的基因 诊断与遗传咨询
遗传性心脏疾病
先天性心脏病 (Congenital Heart Defects,CHD) 遗传性心肌病 (Inherited Cardiomyopathy) 遗传性心律失常 (Inherited arrhythmia disorders)
• 8-10/1,000 births • CHD account for:
– 25% of all congenital malformations – 15% of all infant deaths
• 20% with one CHD will have a second • 25% will have a second malformation
Down Syndrome
• Phenotype:
-宽脸,平剖面,
-短鼻,眼距宽,大舌 -通贯手 -智力落后 • Cardiovascular(~50%)
-Complete AV -Canal -Primum ASD
(often with cleft MV) -VSD -PDA -TOF -DORV
• Week 5-Term: development of the conduction(传导) system
(Days 20-50: the most sensitive time for disturbances in formation of the CV system)
Most CHD multifactorial : Genetic and Environmental
育不全)
• Immune defect (胸腺缺如、甲状
旁腺发育不全)
• Genetics
-Autosomal Dominant -94% Sporadic -95% 22q11 microdeletion -Deletion either 3 Mb long (85%) or 1.5 Mb -Genes thought to be important:
Heart Development
• Week 3: CV System begins to develop
(Days 21-22: Cardiac contractions 收缩 begin)
• Week 3-8: Formation of the heart and major vessels(血管)
Single gene mutation syndromes
Alagille Syndrome
• Cardiovascular Disease: 90-97% • Hepatic Disease • Facial Features: 突出的额头，深陷的眼睛，下巴尖 • 搔痒、生长停滞、“白陶土样”大便 • Autosomal dominant • JAG1 gene, 20p12