Overview of Genetic Syndromes: Etiology, Physical and Behavioral Phenotypes

Transcription

1 Overview of Genetic Syndromes: Etiology, Physical and Behavioral Phenotypes Cynthia M. Powell, MD Professor of Pediatrics and Genetics Chief, Division of Pediatric Genetics and Metabolism The University of North Carolina at Chapel Hill

2 Objectives Understand etiology and examples of numerical chromosome disorders Be familiar with some of the more common microdeletion syndromes Be familiar with the new technique of chromosome microarray and examples of conditions diagnosed with this method Be familiar with behavioral phenotypes of syndromes discussed

3 How to approach the genetic workup of a child with a developmental or psychiatric disorder Family history Psychiatric disorders, intellectual disability, birth defects, miscarriages, stillbirths, consanguinity Cognitive impairment? Yes more likely to have a chromosome abnormality, microdeletion syndrome, Fragile X syndrome, metabolic disorder Physical anomalies As clue to underlying syndrome

4 Importance of the family history as a screening tool in both primary and specialty care settings A family history can help you screen and assess risks in patients and families for genetically influenced conditions such as depression, substance abuse, psychoses - as well as for an increasing number of single gene conditions, some of which have available diagnostic testing and therapeutic and preventive measures

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9 Chromosomes are made up of genes on a string Each chromosome contains thousands of genes

10 Down syndrome Most common single, known cause of intellectual disability (~ 1/800 births). picasaweb.google.com

11 95% of Patients With Down Syndrome Have 3 SEPARATE CHROMOSOME 21s. 47,XY,+21

12 How Do Numerical Abnormalities Occur? Many are due to chromosome segregation errors during meiosis & mitosis Nondisjunction (failure of chromosomes to disjoin normally) is the most common known cause of aneuploidy. Premature Separation of sister chromatids is also known to result in aneuploidy Both monosomies and trisomies result from nondisjunction & premature centromere division Others are due to failed cell division or dispermy Failed cytokinesis (cell division) during mitosis results in tetraploidy & during meiosis results in triploidy Fertilization of a normal haploid egg with two sperm (dispermy)

13 Health Supervision Developmental delay and hypotonia Delayed milestones Speech delay and language problems Mental retardation mild (55-70) to moderate (40-55) IQ range on average Refer for Early Intervention Services to include speech, PT, OT Special education Mainstreaming/Inclusion

14 Health Supervision Vision problems Stabismus (45%), myopia (70%), nystagmus (35%), blocked tear duct (20%), fine lens opacity (59%), cataracts in adults (30-60%) Refer to ophthalmolgist by 6 months of age

15 Health Supervision ENT Hearing loss in 66% Conductive, mixed, sensorineural 60-80% middle ear fluid, most require PE tubes Upper airway obstruction/sleep apnea Hearing screening at birth, if normal, repeat at 6 months and 12 months and then annually

16 Down syndrome Most common single, known cause of mental retardation (~ 1/800 births). See fact sheet. Typical Facies: Round face Upslanting palpebral fissures, epicanthal folds Flat nasal bridge Open mouth w/ protruding tongue secondary to hypotonia Small, dysmorphic low-set ears picasaweb.google.com Figure 10-1, Thompson & Thompson Thompson & Thompson Genetics in Medicine, 7th edition pg 91

17 Down Syndrome Low-set, Characteristic Folding Brushfield Spots Around Iris Margin Short Neck w/ Excess Skin

18 Down Syndrome Mild-Moderate ID (IQ=30-60) Early intervention programs Heart Defects: AVSD, VSD Newborn echo, cardiology eval. GI: Duodenal atresia, Hirschsprung, pyloric stenosis, TE fistula, omphalocele, annular pancreas, imperforate anus Short & broad hands w/ transverse crease & 5 th finger clinodactyly Hip Dislocation Hearing Loss Vision problems pediatric 1yr Endocrine: hypothyroidism Newborn thyroid screen 6mo, then annually) Wide gap between 1 st & 2 nd toes, furrow extending along length Hematologic: leukemia 15X increase, but overall risk < 1%

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20 Turner Syndrome Lymphedema, Cystic hygroma Nuchal fold thickness Lymphedema Webbed neck, nipples widely spaced, carrying angle Short 4th metacarpals

21 Turner Syndrome Magicmom/bianca.html Dr. Catherine Ward, is a geneticist with Turner syndrome at Akron Children's Hospital in Akron, Ohio eries Cardiac Abnormalities Bicuspid aortic valve Aortic dissection Coarctation of aorta Cardiac eval, echo Renal Abnormalities Horseshoe kidney Unilateral renal agenesis Renal ultrasound Short Stature Avg = 4 7 Endocrine, growth hormone tx Delayed Puberty 2 nd sex characteristics Hormone replacement Infertility ART possible Hearing Impairment Learning Disabilities Spatial perception Intervention programs

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23 Other Sex Chromosome Variations Often no phenotypic abnormalities IQs generally in normal range Learning disabilities common High risk of behavioral and psychiatric problems

24 Sex Chromosome Variations: XYY Former model turned novelist Annabel Giles, 49, Annabel's second child, Ted, ten, was born with XYY syndrome, a chromosomal disorder, and here she provides, with extraordinary candour, an account of her life as the single parent of a special needs child. Factor-How-rare-chromosome-disorder-brought-son-worldpain.html Incidence 1/1000 Normal birth weight and length, above average stature Hyperactivity, distractibility, temper tantrums, low frustration tolerance, learning disabilities in some Wide variability

25 Sex Chromosome Abnormalities: XXY, Klinefelter Syndrome Smith s Recognizable Patterns of Human Malformation, 5 th ed. Incidence 1:1000 Variable phenotype Most common lack of secondary sex characteristics Early developmental delay, problems with psychosocial adjustment Verbal IQ lower than performance Shy, immature, reserved, awkward

26 Sex Chromosome Abnormalities: Triple X Incidence 1/1000 Early delays in motor, language and cognitive development Shy, withdrawn, immature, poor coordination Depression Psychosis Wide variability and ascertainment bias

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29 Standard Cytogenetic Techniques Karyotype (G-bands) Evaluation of entire genome Resolution typically limited to 3-5 Mb FISH (Fluorescence in situ hybridization) High resolution usually ~100 kb or less Requires a clinically directed search Search is very specific

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31 DiGeorge or Velocardiofacial Syndrome Facial Features (most) prominent nose w/ squared nasal root, small eyes, small ears w/ abnl folding Abnormal Palate (~70%) overt/submucous cleft Cong. Heart Dis. (~75%) conotruncal malformations Learning (70-90%) pages.aspx?page=439 m/viewarticle/430898_4 Hypocalcemia (40-50%) Immune Deficiency Infections Psychiatric Disorders

32 A Cytogenetically Visible Deletion is Seen in 25% of Patients With DiGeorge Syndrome. 22 del(22)

33 FISH Detects a DiGeorge Syndrome Deletion DiGeorge Critical Region TUPLE1 (HIRA) CONTROL 22. The red TUPLE1 probe which maps to the DiGeorge critical region does not hybridize to the deleted chromosome 22

34 22q Deletion Syndrome Includes velo-cardiofacial syndrome, Shprintzen syndrome, DiGeorge syndrome Variable dysmorphic features, cleft palate, conotruncal heart defects, hypocalcemia, learning disabilities, mild MR, psychiatric disorders

35 22q Deletion Syndrome Behavioral Phenotype Early developmental delay and language impairment Strong concrete skills and poor executive functioning IQ scores decrease Learning disabilities in math and reading comprehension VIQ>PIQ

36 22q Deletion Syndrome Behavioral Phenotype Psychiatric problems ADD +/- hyperactivitiy 20% develop psychosis as adults Lachman et a;/ 1996: COMT (breaks down dopamine) polymorphism low enzyme activity. Hemizygotes for lowactivity allele have severe rapidcycling bipolar disorder Rx: Preventing secretion of dopamine or counteracting action

37 Prader-Willi Syndrome Early hypotonia Short stature Small hands and feet Hypogonadism Intellectual disability Hyperphagia

38 Prader-Willi Syndrome In later childhood, onset of excessive appetite and obesity

39 Prader-Willi Syndrome Incidence 1/15,000 Approximately 70% of cases have a cytogenetic deletion involving proximal chromosome 15 inherited from the father

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41 Prader-Willi Syndrome: Development and Behavior Most have mild intellectual disability Most learn to read and to do simple math Temper tantrums, stubbornness, controlling/manipulative, obsessivecompulsive, food hoarding, skin and rectal picking Autism spectrum disorder in rare cases True psychosis in 5-10% of individuals

42 Angelman Syndrome Incidence 1 in 12,000-20,000 Approximately 70% of patients have a deletion of the same chromosome region (15q11-13) but on the chromosome 15 inherited from the mother

43 Angelman Syndrome Microcephaly Short stature Seizures Frequent unprovoked laughter Severe intellectual disability

44 Approximately 3-5% of patients with Angelman syndrome have two chromosome 15s inherited from the father (paternal UPD)

45 Angelman Syndrome Behavioral Phenotype Cognitive abilities severely to profoundly impaired Receptive language skills higher than expressive Attention deficit and hyperactivity Sleep abnormalities Aggressive behavior often attention-seeking

46 Williams Syndrome Deletion 7q11.23 Elastin gene (ELN) LIM-kinase 1 gene Distinctive facial features Hypercalcemia Supravalvular aortic stenosis Pulmonary artery stenosis

47 Williams Syndrome Behavioral and developmental phenotype Very friendly, ADD, anxiety Low average to severe intellectual disability, most with mild ID

48 Williams Syndrome Behavioral and developmental phenotype Musical ability

49 Smith-Magenis Syndrome p?cat3=931 17p11.2 deletion short stature ID, behavior abnormalities hearing loss synophrys brachydactyly heart defects

50 Clinical Features in Smith- Magenis Syndrome Craniofacial Flat midface Brachycephaly Broad and square face Heavy brows with lateral extension Broad nasal bridge Full nasal tip Broad mouth with full lips Tented upper lip Malformed ears

51 Limbs Clinical Features in Smith- Magenis Syndrome Short fingers Broad hands Hoarse voice Congenital Heart Defects Eye Abnormalities Intellectual disability Seizures

52 Diagnosis of Smith-Magenis Clinical suspicion Chromosome studies Confirm with FISH analysis Syndrome

53 Developmental/Behavioral Phenotype Infantile hypotonia Hyperactivity Self-injurious behavior onychotillomania and polyembolokoilamania Autistic-type behavior Self-hugging Speech delay Sleep disorder hypersomnolence and lethargy in infancy, frequent nocturnal awakenings and fragmented sleep in childhood

54 The Chromosome Microarray Technology Also Detects Copy Number Changes Arrayed DNA probes provide a locus-by-locus measurement of DNA copy number variation at many loci simultaneously Enables us to: Survey the entire genome (like karyotyping) Very high resolution (like FISH)

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58 Case History Two year old male referred by military medical center for: developmental delay Born at 36 weeks to G2P1 18yo mother Pregnancy complicated by preterm labor Mother reported decreased fetal movement compared to her first pregnancy Meconium aspiration

59 Case History Neurology consult at 8 months of age for developmental delay: central hypotonia Normal brain MRI at 9 months Walked at 24 months, limited speech Surgery for ear tubes Right sided hearing loss No other significant illnesses, no loss of skills or regression with illness

60 Findings Child with global delay, mild ataxia clumsiness, some early features of autistic spectrum disorder with limited social interaction and speech, hypotonia Non dysmorphic Growth parameters Height 25 th Weight 10 th Head Circumference 50 th Normal metabolic labs, karyotype, fragile X Microarray: 46, XY, dup(15)(q11.2q13)

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62 15q duplication Duplication of PWACR Phenotype depends on parental origin of duplication Most paternally derived duplications result in normal outcome Maternally derived duplications result in clinical phenotype Estimated prevalence in patients evaluated for autism (with normal Fragile X studies): 1/200-1/600

63 15q duplication Clinical Features Autistic spectrum disorder Communication disorder Developmental delay Hypotonia Ataxia Seizures Mild to no dysmorphic features Macrocephaly, joint laxity

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65 The American Journal of Human Genetics 90, , May 4, 2012

66 Shank genes (1,2 and 3) encode proteins that are involved in the formation and function of neuronal synapsis. All three have now been implicated in ASD.

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68 BREAST CANCER Research and Individualized Therapy Gene Expression

69 Next Generation Sequencing

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71 Sanger vs. whole-exome sequencing: Technical considerations Sanger bp Targeted mutation analysis Complete coverage Gold standard WES 30 Mb in exome (3 billion in entire genome) Mutation fishing in many targets Interpretation difficulties Not considered reliable enough to use without confirmation

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73 Patient NCG_00183: muscular dystrophy

74 Conclusions Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.)

75 North Carolina Newborn Exome Sequencing as Universal Screening (NC NEXUS) UNC-CH SOM one of 4 grantees in U.S. jointly funded by NHGRI and NICHD

76 INCIDENTAL FINDINGS Testing can identify things that are not related to the original intent of testing ( incidental findings ) With next gen sequencing these can include mutations in genes such as those for breast or colon cancer, cardiac arrhythmias, intellectual disability, etc.. What should be reported back to patients/families?

77 Types of Genetic Testing Diagnostic Predictive Susceptibility

78 Genetic Testing: Ethical Issues Genetic testing is different Implications for other family members Genetic testing of minors Privacy and discrimination issues

79 Privacy and Discrimination GINA: Genetic Information Non- Discrimination Act Passed and signed into law in 2008 Will take effect in 2009 To prevent discrimination in health insurance and employment based on genetic information May 21, 2008: Signed into law Health insurance to take effect by May 2009 and employers November 2009

80 Federal Legislation GINA What it does not include Members of the military Life insurance, disability insurance, longterm care insurance

81 Patient Protection and Affordable Care Act Signed into law by President Obama on March 23, 2010 Prohibits insurance companies from denying coverage of children under the age of 19 based on pre-existing conditions. Effective now. Prohibiting insurance companies from rescinding coverage. Effective now. Providing free preventive care (all new plans must cover mammograms, colonoscopies, etc.) Effective now. Providing access to insurance for uninsured Americans with pre-existing conditions. Will provide new coverage options to individuals who have been uninsured for at least six months because of a pre-existing condition. States have the option of running this new program in their state. If a state chooses not to do so, a plan will be established by the Department of Health and Human Services in that state. Effective now. Prohibiting discrimination due to pre-existing conditions or gender. The law implements strong reforms that prohibit insurance companies from refusing to sell coverage or renew policies because of an individual s pre-existing conditions. Also, in the individual and small group market, the law eliminates the ability of insurance companies to charge higher rates due to gender or health status. Effective January 1, 2014.

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