以4种单基因病遗传咨询和诊断为例初探我院遗传咨询规范化程序
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摘要
研究背景：
在中国,人口基数大,人口增长快。据国家人口计生委统计,我国平均每30秒就有一名缺陷儿出生。及时有效地查找出生缺陷的病因,以采取积极有效的措施减少或避免缺陷儿出生,是我国及世界各国面临的一个巨大难题。导致出生缺陷的病因包括环境因素、孕妇因素及遗传因素等。其中,遗传性因素所致的出生缺陷占总出生缺陷致病因素的25%。目前,减少或避免遗传性出生缺陷的最有效的防治措施就是禁止近亲结婚和对已发现的遗传病进行遗传学诊断、遗传咨询和优生指导。
遗传咨询是一个帮助人们理解并接受遗传因素对疾病的作用以及该作用对医学,心理和家庭方面的影响的程序。该程序包括：1.通过对家族史和现病史的解释来评估疾病的发生或再发风险率；2.进行有关疾病的遗传性质,实验室检测,治疗处理和预防的教育,并提供有关疾病的各种可以求助的渠道和相关研究现状及进展；3.辅导促进知情选择和促进患者逐步认知和接受所患疾病及其再发风险。
目前,我国尚未建立正规的临床遗传咨询执业资格认证体系,与欧美发达国家相比,我国临床遗传服务的现状,不论是在遗传病诊断水平上还是在遗传咨询质量上,都存在相当大的差距。
因此,如何提高遗传病的诊断水平及遗传咨询的质量,以降低遗传病及出生缺陷发生率,是我国当前亟待解决的问题。
研究目的：
以提高遗传病诊断水平和遗传咨询质量为目的,初步探讨我院临床遗传咨询规范化程序。
研究方法：
借助我院的已有的临床遗传服务平台,以我院新发现的4种单基因病的诊断与遗传咨询为例,对我院遗传咨询的规范化程序进行初步探讨,并尝试草拟我院遗传病诊断与遗传咨询规范化程序(建议稿)。
研究对象：
4种单基因遗传病。
病例1：以“四肢乏力28年”为主诉的28岁女性患者,要求遗传咨询和生育咨询。
病例2：以“生长发育迟缓伴智力低下7余年”为主诉的7余岁男孩,其父母欲再生育,要求遗传咨询。
病例3：以“发现身材矮小20余年”为主诉的29岁男性患者,已婚,欲生育。
病例4：以“夜盲10余年”为主诉的13岁女孩,其父母欲再生育,要求遗传咨询。
研究结果：
病例1：患者诊断为中央核肌病,由DNM2基因第8外显子c.1105C>T；pR369W杂合性错义突变所致。解释患者在妊娠期间可能有出现限制性通气障碍、呼吸衰竭、肺部感染、甚至肺源性心功能衰竭的风险,而胎儿可能有宫内慢性缺氧和宫内发育迟缓的风险。为了降低和预防上述可能风险,我们积极地与外院心内科、呼吸科等多个学科进行对话和沟通,以加强各个学科间的交叉合作等,并提供各种可以求助的渠道和相关研究现状和进展。
病例2：患者“生长发育迟缓伴智力低下”的症状系为先天性肾性尿崩症的严重并发症之一。对AVPR2基因进行突变筛查,发现第2外显子c.506T>C；pL169P的半合子错义突变。向患者家属解释该病为X-连锁隐性遗传,并解释夫妻若再生育其后代再发风险率,目前的治疗方法及预防的措施等。
病例3：患者诊断为X-连锁迟发性脊柱骨骺发育不良,为SEDL基因上一个包括第6外显子在内的大小为1,327bp的半合子缺失突变所致。向患者及其家属解释该病为X-连锁隐性遗传,后代再发风险率,治疗方法及预防的措施等。
病例4：患者诊断为先天性静止性夜盲症(小口氏病型),为SAG基因上第8外显子杂合性无义突变c.577C>T；pR193X及包括第2外显子在内的大小为3,224bp的杂合性缺失所致。向患者及其家属解释该病为常染色体隐性遗传,并解释后代再发风险率,目前的治疗方法及预防的措施等。
2.基于对新发现的4种遗传病诊断和遗传咨询,尝试起草我院以提高遗传病的诊断率为目的的临床实践操作规范(建议稿)和我院以提高遗传咨询质量为目的的临床实践操作规范(建议稿)。
结论：
1.通过对4种不同遗传病的诊断与遗传咨询的临床实践,本人掌握了对新发现遗传病诊断和遗传咨询的能力,并在我院建立了这4种遗传病的诊断和遗传咨询的平台,为我院开展这4种遗传病的基因诊断及遗传咨询的服务项目奠定前提基础。
2.发现了3个新的突变。其中,SAG基因缺失突变是世界上报道的第1例,其导致的先天性静止性夜盲症(小口氏病型)也是中国报道的第1例。
3.在对女性患者的生育咨询中,强调综合评估疾病与妊娠的相互作用、相互影响,评估胎儿及患者围产期可能发生的各种风险、有无预防方法及有效处理措施等；强调应与心血管科,呼吸科,妇产科等多个学科密切合作,相互配合。
4.起草了我院遗传病诊断和遗传咨询的临床实践操作规范(建议稿),有利于提高我院遗传病诊断水平和遗传咨询质量,并为我院正式的临床遗传咨询规范化程序的出台,起到一个抛砖引玉的作用。
Background:
China has a large number of people and a rapid growth in its population. According to the statistic data from State Family Planning Commission (SPFPC), there is a baby with birth defects born every30seconds in China, on average. At the moment, it is a great problem for China and other parts of the world to figure out a timely and effective way of establishing the causes of birth defects and taking effective actions to decrease or prevent the birth defects. Causes of birth defects may contain environmental factors, pregnancy factors, and genetic factors and so on, among which the genetic factors may account for25%of total causes of birth defects. Now, one of the most effective ways to decrease or prevent birth defects is to prohibit consanguineous marriages, make genetic diagnosis, and provide genetic counseling and eugenic advice for inherited diseases.
With a right genetic diagnosis, the genetic counseling will act with a well-defined objective in mind. Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates the following:1. Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.2. Education about inheritance, testing, management, prevention, resources and research.3. Counseling to promote informed choices and adaptation to the risk or condition.
So far, no formal credential programs or board to certificate genetic counselors or clinical geneticist in China. Compared with the developed countries in the Europe and in the America, the current status of clinical genetic service in China has quite a long distance in the level of genetic diagnosis and the quality of genetic counseling of inherited diseases.
Therefore, the question how to improve the quality of clinical diagnosis, counseling and eugenic advice for inherited disease is urgently to be solved in China, in order to prevent genetic disease or birth defects.
Purposes:
This was a pilot study of a standardized procedure for clinical genetic counseling in our hospital, in order to further improve the diagnostic skills of inherited disease and the quality of genetic counseling in our hospital.
Methods:
On the present platform of clinical genetic service in our hospital, we were to preliminarily explore a standardized procedure for genetic counseling, using four different cases of genetic counseling and genetic diagnosis as examples, and tried to draft a standardized procedure of the clinical practices for genetic counseling and genetic diagnosis (recommendations).
Subjects:
Four different cases of inherited diseases.
Case1:A28-year old female patient with a main complaint of generalized muscle weakness for28years came to our hospital for genetic counseling and family planning consultations.
Case2:A7-year old boy was referred as growth retardation and intellectual disability for7years. His parents planned to have another baby, asking for genetic counseling.
Case3:A29-year old male patient with a main complaint of short stature for20years was married and planning to have children, inquiring for genetic risks.
Case4:A13-year old girl came with a main complaint of night-blindness for around10years. Her parents wanted another child, asking for genetic counseling.
Results:
Case1:The female patient got a definite genetic diagnosis of centronuclear myopathy with a heterozygous missense mutation c.1105C>T; pR369W (CGG>TGG) in the exon8of DNM2gene. We explained to the patient and her family members that risks of restricted ventilation function disturbance, respiratory failure, pulmonary infection and even pulmonary heart failure may occur in the patient during peripartum, and risks of chronic intrauterine hypoxia and introuterine growth retardation for the fetus may occur during the period. And we actively make close contact and interact with multiple disciplines in other comprehensive hospitals such as cardiovascular department, respiratory department and so on to facilitate the collaboration and coordination of a multidisciplinary team, and provided some resources for help and the information of current researches about it, in order to decrease or prevent the above possible risks.
Case2:The symptom of grow retardation and intellectual disability in the boy was considered as one of the severe complications of congenital nephrogenic diabetes insipidus, caused by a hemizygous missense mutation c.506T>C; pL169P (CTT>CCT) in the exon2of AVPR2gene. We explained to the boy's parents the X-liked recessive inheritance of the disorder; the recurrent risk for the next pregnancy of the boy's parents, current treatments available and optional preventions and so on.
Case3:The male patient was diagnosed to have spondyloepiphyseal dysplasia tarda with a hemizygous deletion of1,327bp containing exon6of SEDL gene. We explained to the patient and his family members the X-liked recessive inheritance of the disorder; recurrent risk, current treatments available and optional preventions and so on.
Case4:The girl got a definite genetic diagnosis of congenital stationary night-blindness (Oguchi's disease) caused by compound heterozygosity of a nonsense mutation c.577C>T; R193X and a heterozygous deletion of3,224bp encompassing exon2in the SAG gene. We explained to the patient and her family members the autosomal recessive inheritance of the disorder; recurrent risk of the girl's parents, current treatments available and optional preventions and so on.
2. Based on the successful experience from the clinical practice of genetic diagnosis and genetic counseling for these four new cases, this study had tried to draft a standardized procedure of clinical practice aimed at improving the diagnostic skills for inherited diseases (recommendations) and the quality of genetic counseling (recommendations), in respective.
Conclusions:
1. Through the clinical practice of genetic diagnosis and genetic counseling for four different inherited diseases, I gained an ability of how to make genetic diagnosis and provide genetic counseling for new inherited diseases. A platform of genetic diagnosis and genetic counseling for these four inherited diseases were established in our hospital, which would lay a foundation for the development of the clinical genetic service of genetic diagnosis and genetic counseling for these four diseases.
2. Three novel mutations were identified. Among them, the deletion mutation in SAG gene was the first report in the world and it was first case of congenital stationary night-blindness (Oguchi's disease) in China.
3. We emphasized the importance of comprehensive evaluations and explanations for the possible interactions between the disease and pregnancy to assess all possible risks to the fetus and the pregnant mother during peripartum, available preventive approaches and effective measures and so on, in terms of family planning consultations for female patients. We also emphasized the importance of close cooperation and coordination with multiple departments including gynecology, cardiology, and respiration and so on.
4. A standardized procedure of genetic diagnosis and genetic counseling in our hospital (recommendations) was drafted, which would improve the diagnostic skills and the quality of genetic counseling in our hospital. We hoped the drafts would throw out a minnow to catch a whale for the formal establishment of a standardized program of clinical genetic counseling in our hospital.
在中国,人口基数大,人口增长快。据国家人口计生委统计,我国平均每30秒就有一名缺陷儿出生。及时有效地查找出生缺陷的病因,以采取积极有效的措施减少或避免缺陷儿出生,是我国及世界各国面临的一个巨大难题。导致出生缺陷的病因包括环境因素、孕妇因素及遗传因素等。其中,遗传性因素所致的出生缺陷占总出生缺陷致病因素的25%。目前,减少或避免遗传性出生缺陷的最有效的防治措施就是禁止近亲结婚和对已发现的遗传病进行遗传学诊断、遗传咨询和优生指导。
遗传咨询是一个帮助人们理解并接受遗传因素对疾病的作用以及该作用对医学,心理和家庭方面的影响的程序。该程序包括：1.通过对家族史和现病史的解释来评估疾病的发生或再发风险率；2.进行有关疾病的遗传性质,实验室检测,治疗处理和预防的教育,并提供有关疾病的各种可以求助的渠道和相关研究现状及进展；3.辅导促进知情选择和促进患者逐步认知和接受所患疾病及其再发风险。
目前,我国尚未建立正规的临床遗传咨询执业资格认证体系,与欧美发达国家相比,我国临床遗传服务的现状,不论是在遗传病诊断水平上还是在遗传咨询质量上,都存在相当大的差距。
因此,如何提高遗传病的诊断水平及遗传咨询的质量,以降低遗传病及出生缺陷发生率,是我国当前亟待解决的问题。
研究目的：
以提高遗传病诊断水平和遗传咨询质量为目的,初步探讨我院临床遗传咨询规范化程序。
研究方法：
借助我院的已有的临床遗传服务平台,以我院新发现的4种单基因病的诊断与遗传咨询为例,对我院遗传咨询的规范化程序进行初步探讨,并尝试草拟我院遗传病诊断与遗传咨询规范化程序(建议稿)。
研究对象：
4种单基因遗传病。
病例1：以“四肢乏力28年”为主诉的28岁女性患者,要求遗传咨询和生育咨询。
病例2：以“生长发育迟缓伴智力低下7余年”为主诉的7余岁男孩,其父母欲再生育,要求遗传咨询。
病例3：以“发现身材矮小20余年”为主诉的29岁男性患者,已婚,欲生育。
病例4：以“夜盲10余年”为主诉的13岁女孩,其父母欲再生育,要求遗传咨询。
研究结果：
病例1：患者诊断为中央核肌病,由DNM2基因第8外显子c.1105C>T；pR369W杂合性错义突变所致。解释患者在妊娠期间可能有出现限制性通气障碍、呼吸衰竭、肺部感染、甚至肺源性心功能衰竭的风险,而胎儿可能有宫内慢性缺氧和宫内发育迟缓的风险。为了降低和预防上述可能风险,我们积极地与外院心内科、呼吸科等多个学科进行对话和沟通,以加强各个学科间的交叉合作等,并提供各种可以求助的渠道和相关研究现状和进展。
病例2：患者“生长发育迟缓伴智力低下”的症状系为先天性肾性尿崩症的严重并发症之一。对AVPR2基因进行突变筛查,发现第2外显子c.506T>C；pL169P的半合子错义突变。向患者家属解释该病为X-连锁隐性遗传,并解释夫妻若再生育其后代再发风险率,目前的治疗方法及预防的措施等。
病例3：患者诊断为X-连锁迟发性脊柱骨骺发育不良,为SEDL基因上一个包括第6外显子在内的大小为1,327bp的半合子缺失突变所致。向患者及其家属解释该病为X-连锁隐性遗传,后代再发风险率,治疗方法及预防的措施等。
病例4：患者诊断为先天性静止性夜盲症(小口氏病型),为SAG基因上第8外显子杂合性无义突变c.577C>T；pR193X及包括第2外显子在内的大小为3,224bp的杂合性缺失所致。向患者及其家属解释该病为常染色体隐性遗传,并解释后代再发风险率,目前的治疗方法及预防的措施等。
2.基于对新发现的4种遗传病诊断和遗传咨询,尝试起草我院以提高遗传病的诊断率为目的的临床实践操作规范(建议稿)和我院以提高遗传咨询质量为目的的临床实践操作规范(建议稿)。
结论：
1.通过对4种不同遗传病的诊断与遗传咨询的临床实践,本人掌握了对新发现遗传病诊断和遗传咨询的能力,并在我院建立了这4种遗传病的诊断和遗传咨询的平台,为我院开展这4种遗传病的基因诊断及遗传咨询的服务项目奠定前提基础。
2.发现了3个新的突变。其中,SAG基因缺失突变是世界上报道的第1例,其导致的先天性静止性夜盲症(小口氏病型)也是中国报道的第1例。
3.在对女性患者的生育咨询中,强调综合评估疾病与妊娠的相互作用、相互影响,评估胎儿及患者围产期可能发生的各种风险、有无预防方法及有效处理措施等；强调应与心血管科,呼吸科,妇产科等多个学科密切合作,相互配合。
4.起草了我院遗传病诊断和遗传咨询的临床实践操作规范(建议稿),有利于提高我院遗传病诊断水平和遗传咨询质量,并为我院正式的临床遗传咨询规范化程序的出台,起到一个抛砖引玉的作用。
Background:
China has a large number of people and a rapid growth in its population. According to the statistic data from State Family Planning Commission (SPFPC), there is a baby with birth defects born every30seconds in China, on average. At the moment, it is a great problem for China and other parts of the world to figure out a timely and effective way of establishing the causes of birth defects and taking effective actions to decrease or prevent the birth defects. Causes of birth defects may contain environmental factors, pregnancy factors, and genetic factors and so on, among which the genetic factors may account for25%of total causes of birth defects. Now, one of the most effective ways to decrease or prevent birth defects is to prohibit consanguineous marriages, make genetic diagnosis, and provide genetic counseling and eugenic advice for inherited diseases.
With a right genetic diagnosis, the genetic counseling will act with a well-defined objective in mind. Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates the following:1. Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.2. Education about inheritance, testing, management, prevention, resources and research.3. Counseling to promote informed choices and adaptation to the risk or condition.
So far, no formal credential programs or board to certificate genetic counselors or clinical geneticist in China. Compared with the developed countries in the Europe and in the America, the current status of clinical genetic service in China has quite a long distance in the level of genetic diagnosis and the quality of genetic counseling of inherited diseases.
Therefore, the question how to improve the quality of clinical diagnosis, counseling and eugenic advice for inherited disease is urgently to be solved in China, in order to prevent genetic disease or birth defects.
Purposes:
This was a pilot study of a standardized procedure for clinical genetic counseling in our hospital, in order to further improve the diagnostic skills of inherited disease and the quality of genetic counseling in our hospital.
Methods:
On the present platform of clinical genetic service in our hospital, we were to preliminarily explore a standardized procedure for genetic counseling, using four different cases of genetic counseling and genetic diagnosis as examples, and tried to draft a standardized procedure of the clinical practices for genetic counseling and genetic diagnosis (recommendations).
Subjects:
Four different cases of inherited diseases.
Case1:A28-year old female patient with a main complaint of generalized muscle weakness for28years came to our hospital for genetic counseling and family planning consultations.
Case2:A7-year old boy was referred as growth retardation and intellectual disability for7years. His parents planned to have another baby, asking for genetic counseling.
Case3:A29-year old male patient with a main complaint of short stature for20years was married and planning to have children, inquiring for genetic risks.
Case4:A13-year old girl came with a main complaint of night-blindness for around10years. Her parents wanted another child, asking for genetic counseling.
Results:
Case1:The female patient got a definite genetic diagnosis of centronuclear myopathy with a heterozygous missense mutation c.1105C>T; pR369W (CGG>TGG) in the exon8of DNM2gene. We explained to the patient and her family members that risks of restricted ventilation function disturbance, respiratory failure, pulmonary infection and even pulmonary heart failure may occur in the patient during peripartum, and risks of chronic intrauterine hypoxia and introuterine growth retardation for the fetus may occur during the period. And we actively make close contact and interact with multiple disciplines in other comprehensive hospitals such as cardiovascular department, respiratory department and so on to facilitate the collaboration and coordination of a multidisciplinary team, and provided some resources for help and the information of current researches about it, in order to decrease or prevent the above possible risks.
Case2:The symptom of grow retardation and intellectual disability in the boy was considered as one of the severe complications of congenital nephrogenic diabetes insipidus, caused by a hemizygous missense mutation c.506T>C; pL169P (CTT>CCT) in the exon2of AVPR2gene. We explained to the boy's parents the X-liked recessive inheritance of the disorder; the recurrent risk for the next pregnancy of the boy's parents, current treatments available and optional preventions and so on.
Case3:The male patient was diagnosed to have spondyloepiphyseal dysplasia tarda with a hemizygous deletion of1,327bp containing exon6of SEDL gene. We explained to the patient and his family members the X-liked recessive inheritance of the disorder; recurrent risk, current treatments available and optional preventions and so on.
Case4:The girl got a definite genetic diagnosis of congenital stationary night-blindness (Oguchi's disease) caused by compound heterozygosity of a nonsense mutation c.577C>T; R193X and a heterozygous deletion of3,224bp encompassing exon2in the SAG gene. We explained to the patient and her family members the autosomal recessive inheritance of the disorder; recurrent risk of the girl's parents, current treatments available and optional preventions and so on.
2. Based on the successful experience from the clinical practice of genetic diagnosis and genetic counseling for these four new cases, this study had tried to draft a standardized procedure of clinical practice aimed at improving the diagnostic skills for inherited diseases (recommendations) and the quality of genetic counseling (recommendations), in respective.
Conclusions:
1. Through the clinical practice of genetic diagnosis and genetic counseling for four different inherited diseases, I gained an ability of how to make genetic diagnosis and provide genetic counseling for new inherited diseases. A platform of genetic diagnosis and genetic counseling for these four inherited diseases were established in our hospital, which would lay a foundation for the development of the clinical genetic service of genetic diagnosis and genetic counseling for these four diseases.
2. Three novel mutations were identified. Among them, the deletion mutation in SAG gene was the first report in the world and it was first case of congenital stationary night-blindness (Oguchi's disease) in China.
3. We emphasized the importance of comprehensive evaluations and explanations for the possible interactions between the disease and pregnancy to assess all possible risks to the fetus and the pregnant mother during peripartum, available preventive approaches and effective measures and so on, in terms of family planning consultations for female patients. We also emphasized the importance of close cooperation and coordination with multiple departments including gynecology, cardiology, and respiration and so on.
4. A standardized procedure of genetic diagnosis and genetic counseling in our hospital (recommendations) was drafted, which would improve the diagnostic skills and the quality of genetic counseling in our hospital. We hoped the drafts would throw out a minnow to catch a whale for the formal establishment of a standardized program of clinical genetic counseling in our hospital.
引文
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