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1 Genetics of the Hemoglobinopathies & Newborn Screening for the Hemoglobinopathies 张咸宁 Tel: ; Office: C303, Teaching Building 2017/03

2 Required Reading Nussbaum RL, et al., 张咸宁等主编 Thompson & Thompson Genetics in Medicine, 第 8 版 ( 双语版 ), 北京大学医学出版社,2016 pp ; Clinical Case Studies-44. Thalassemia 陈竺, 主编 : 医学遗传学, 第 3 版 pp 人民卫生出版社,2015

3 Part I. Genetics of the Hemoglobinopathies 血红蛋白病

4 患儿,G1P1, 女,5 岁 6 个月, 父母均为广东韶关人, 均为汉族, 就诊时母亲已孕第 2 胎 ( 妊娠 12 周 ), 患儿为足月正常分娩, 出生时正常, 婴儿期吃奶常吐, 夜睡眠中易哭闹, 平时易感冒, 约 2 岁时因感冒发热在当地医院留医, 被诊断为地中海贫血, 住院输血一次, 此后至今类似情况在当地医院输血 10 次血细胞计数资料 (2 岁 ):Hb 62 g/l,rbc 参数 :MCV 73.5 fl MCH 20.3 pg 半年前, 血细胞计数资料 :Hb 78.0 g/l,rbc 参数 :MCV 76.5 fl MCH 21.5 pg 查体 : 身高 81 cm, 体重 11 kg, 脸色苍白, 巩膜稍黄, 腹部稍膨大, 肝肋下可触及, 脾肋下 1 指, 质软, 无明显头颅和面部骨骼畸形, 无智力障碍要求对现怀孕的第二胎进行产前诊断

5 患儿, 男,3 岁 10 个月, 父母均为广西东兴人, 分别为汉族 ( 父 ) 和壮族 ( 母 ) 人, 母亲抱孩子就诊, 诉孩子为第一胎, 家族中患儿大姨妈曾生育过类似女孩, 出生时足月正常分娩,8 个月时开始发病, 食欲不佳, 睡眠差, 常夜汗和吵闹, 平时易感冒,10 个月时在当地医院因感冒发热住院, 第一次输血, 此后 10 余次因发热在当地医院输血当地医院血细胞计数资料 (2 岁 ),Hb 54 g/l,rbc 参数 :MCV 62.5 fl MCH 24.3 pg Rtc 87.3( 10 9 /L) 查体 : 身高 80 cm, 体重 10.5 kg, 脸色苍白, 巩膜黄染, 腹部膨大, 肝肋下 1 指, 脾肋下 2 指, 质软, 无明显头颅和面部骨骼畸形, 鼻梁低, 无智力障碍

6 Learning Objectives 1. To review the normal structure-function relationships of Hb and expression of globin genes 2. To examine the hemoglobinopathies as disorders of Hb structure, or α- or β-globin gene expression 3. To explore the influences of compound heterozygosity and modifier genes on hemoglobinopathy phenotypes

7 Compound heterozygote( 复合杂合子 ): An individual, or a genotype, with two different mutant alleles at the same locus Compound heterozygote homozygote Double heterozygote

8 Molecular Disease( 分子病 ) A disease in which there is an abnormality in or a deficiency of a particular molecule, such as hemoglobin in sickle cell anemia 酶蛋白病 (enzymopathy. 先天性代谢缺陷 ): Any of a group of congenital disorders caused by an inherited defect in a single specific enzyme that results in a disruption or abnormality in a specific metabolic pathway 常隐 (AR)

9 生化遗传病血红蛋白病 : 镰状细胞贫血地中海贫血血浆蛋白病 : 血友病酶蛋白病 : 氨基酸代谢病糖代谢病脂类代谢病嘌呤代谢病卟啉代谢病和尿素循环障碍病等受体蛋白病 : 家族性高胆固醇血症膜转运载体蛋白病 :CF 结构蛋白病 :DMD OI( 成骨不全 )

10 Hemoglobinopathies 血红蛋白病 The most common single gene disorders in the world WHO: 5% of the world s population are carriers for clinically significant hemoglobinopatihies Well understood at biochemical and molecular levels

11 HbA: α 2 β 2 / HbF: α 2 γ 2 Globular tetramer MW 64.5 kd α-chain 16p13.3 Polypeptide length of 141 amino acids β-chain 11p15.4 Polypeptide length of 146 amino acids

12 Globin Tertiary Structure

13 Gene cluster 基因簇 : 基因家族中来源相同结构相似和功能相关的在染色体上彼此紧密连锁的一组基因 Pseudogene 假基因 : DNA sequence homologous with a known gene but is non-functional

16 Developmental Expression of Globin Genes and Globin Switching ( 发育时珠蛋白基因的表达和珠蛋白的转换 )

18 The normal human Hbs at different stages of Stage in development Embryonic development Hb Structure Proportion in normal adult (%) Gower I ζ 2 ε 2 - Gower II α 2 ε 2 - Portland I ζ 2 γ 2 - Fetal F α 2 γ 2 <1 Adult A α 2 β α 2 δ 2 2-3

19 Clinic Disease: Influences of Gene Dosage and Developmental Expression Dosage 4 α- vs. 2 β-globin alleles per diploid genome Therefore, mutations required in 4 α-globin alleles compared with 2 β-globin alleles for same 100% loss of function Ontogeny( 个体发育 ) α expressed before vs. β expressed after birth Therefore, α-chain mutations have prenatal consequences, but β-chain mutations are not evidenced even in the immediate postnatal period

20 Genetic disorders of Hb 1. Structural variant: alter the globin polypeptide without affecting its rate of synthesis 2. Thalassemia: reduced rate of production of one or more globin chains 3. Hereditary persistence of fetal hemoglobin (HPFH. 遗传性胎儿血红蛋白持续症 ) : a group of clinically benign conditions, impairing the perinatal switch from γ- to β-globin synthesis

21 There are >400 structural variants

23 HbS is the first variant to be discovered (1949) Its main reservoir is Central Africa where the carrier rate approximates 20%. (Heterozygous advantage) Approximately 8% of African- Americans will carry one sickle gene.

25 Thalassemia: An imbalance of globin-chain synthesis Hb synthesis characterized by the absence or reduced amount of one or more of the globin chains of Hb α-thalassemia β-thalassemia

26 地贫 : 珠蛋白合成不平衡性贫血 α γ β β-thalassemia (α/β+γ ) Normal α-thalassemia (α/β+γ ) α- 地贫导致 α / 非 α 链比例下降 β- 地贫引起 α / 非 α 链比例上升

30 Hb Barts (hydrops fetalis 水肿胎儿 )

32 Hb Barts 胎儿水肿综合征最常见于中国和东南亚

33 β-thalassemia:underproduction of the β-chain. β-thal trait (β + / β or β 0 /β) :.asymptomatic (β + :reduced;β 0 : absent) β-thal intermedia (β + / β + ):. moderate anemia β-thal major (β 0 /β 0 orβ + /β 0 or β + / β + ) :. severe anemia during the first two years of life. hepatosplenomegaly. growth failure. jaundice. thalassemic facies

35 Thalassemias can arise in the following ways: 1. One or more of the genes coding for hemoglobin chains is deleted. 2. A nonsense mutation that produces a shortened chain. 3. A frameshift mutation that produces a nonfunctional chain. 4. A mutation may have occurred outside the coding regions.

36 β- globin gene and β-thalassemia

37 复合杂合子 (compound heterozygote):an individual, or a genotype, with two different mutant alleles at the same locus 指在 2 条同源染色体的相同基因座上 2 个等位基因的不同突变组成的杂合基因型细胞或个体意即其突变基因型非一般所标示的 aa, 而实际为 aa Compound heterozygote homozygote Double heterozygote 复合杂合子多见于 AR 遗传病 ( 如 β- 地贫 ) 例如,1 个双亲罹患 β- 地贫, 另 1 个双亲罹患镰状细胞贫血, 其子女为复合杂合子

38 双重杂合子 (double heterozygote): 指一个细胞或个体的 2 个不同的基因座分别含有 2 个不同的杂合等位基因即双重杂合子的基因型为 AaBb, 是 2 种不同的常染色体隐性遗传病的突变等位基因的携带者 ( 不患病 ) 例如,1 个双亲罹患 α- 地贫, 另 1 个双亲罹患镰状细胞贫血, 其子女为双重杂合子

40 Part II. Newborn Screening for the Hemoglobinopathies

41 Learning Objectives 1. To review the evolving principles of newborn screening 2. To examine newborn screening (NBS) for the hemoglobinopathies 3. To understand the appropriate response to a positive hemoglobinopathy NBS 4. To appreciate the role of clinical follow-up for the hemoglobinopathies

42 Population-Based Screening

43 Genetic Screening: 从一个群体中鉴别和选择出某种基因或基因型的过程 Population-based approach to identify individuals with certain genotypes known to be Associated with a genetic disease, or Predisposition to a genetic disease Disorder targeted may affect Individuals being screened, or Their descendents

44 Objective of Population Screening To examine all members of the population designated for screening Carried out without regard for family history Should not be confused with testing for affected individuals or carriers within families ascertained because of a positive family history

45 Genetic Screening Important public health activity Will have increasingly significant role with availability of more and better screening tests for Genetic diseases Diseases with an identifiable genetic component Critical strategic hurdle for implementation Venue in which to capture 100% of target population

46 Principles of Newborn Screening (NBS)

47 NBS Public health governmental programs Population screening for all neonates Intervention Prevents or at least ameliorates consequences of targeted disease Cost-effective Controversial Not simply a test, but a system

48 Evolving NBS Criteria 1. Treatment available Not always Example: Tandem Mass Spectrometry (MS/MS) 串联质谱法 Analogy: Childhood cancer (75% survival) and protocol-driven iterative improvements 2. Pre-symptomatic treatment effective No Example: For rarer hemoglobinopathies may not have accurate knowledge of natural hx

49 Evolving NBS Criteria 3. Clinical ascertainment not effective, so test required Not always Example: G6-PD deficiency and kernicterus( 核黄疸 ) Problem: Clinical ascertainment is never 100% 4. Rapid and effective lab test available No Example: Severe combined immunodeficiency (SCID) Problems: Limited federal funding for test development until recently, and low cost and margin limit corporate interest

50 Evolving NBS Criteria 5. Screening is cost-effective Not always Examples: All but PKU and congenital hypothyroidism Problems: Standard not required or met for adult-onset disorders 6. System infrastructure in place Variable Example: Practitioner- and state-based Problems: Some states fund only the test and not the follow-up, and sub-specialists not available in every state

51 Role for Federal Government in NBS System Oversight All states and DC (USA) screen for PKU, congenital hypothyroidism, galactosemia and hemoglobinopathies, but that is the only disease-target uniformity National agenda for NBS Recommended by NBS Taskforce in 1999 A specific agenda recommended by American College of Medical Genetics in 2004

626 139 genotype phenotype

thalassemia Watson Crick 1953 neucleic acid 3 10 9 46 mitochondria Mckusick 2208 2136 4344 1988 2208 1433 626 139 genotype phenotype peptide chain 1 2 2 HbA 2 HbA2 thalassemia (1) (2) (3) (4) MCV mean