General Genetics and New Technologies in Testing

Transcription

1 General Genetics and New Technologies in Testing B3 Karlene Coleman, RN, MN, CGC Certified Genetics Counselor Children s Healthcare of Atlanta, Atlanta, GA Clinical Instructor Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, GA The speaker has signed a disclosure form and indicated she has no significant financial interest or relationship with companies or the manufacturer(s) of any commercial product/service that will be discussed as part of this presentation. Session Summary This session will provide an overview of the main patterns of inheritance, including chromosomal, single gene, and multifactorial. New technologies in testing will be included. Session Objectives Upon completion of this presentation, the participant will be able to: define the terms trigonocephaly, brachycephaly, plagiocephaly and scaphocephaly, including the suture that causes these head shapes; describe how to measure the inner canthus, outer canthus and inter-pupillary distances; define the difference between hypertelorism and hypotelorism label a diagram of the ear with the root, upper helix, and lobe; write the best way to determine if an ear is normally placed or low set; describe one way to determine if micrognathia is present; correctly write the formula for determining if the nipples are wide-spaced; identify the three main palmar creases and name the two creases that make up a single transverse palmar crease (when it is present); describe the difference between pre-axial and post-axial polydactyly; identify the best test that would look for a major trisomy (13, 18 or 21); identify the best test to order if there are multiple dysmorphic features but no clear syndrome or major trisomy is suspected; write the correct genetic disorder that would be suspected in a hypotonic newborn with absent DTRs. B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 1 of 24

2 Test Questions 1. A newborn with trigonocephaly has which suture fused? a. Metopic b. Coronal c. Sagittal d. Lambdoidal 2. Nipples are considered to be wide-spaced when they are greater than what percentage of the total chest circumference? a. >23 percent b. >25 percent c. >27 percent d. < 30 percent 3. Hypertelorism is determined which of the following measurements? a. inner canthal b. outer canthal c. interpupillary d. a ratio between the inner canthal and outer canthal 4. Excessively long digits are called what? a. camptodactyly b. ectrodactyly c. syndactyly d. arachnodactyly 5. Infants with Spinal Muscular Atrophy will have which features? a. inability of the muscles to relax after a contraction b. tented mouth and poor respiratory effort in the delivery room c. abnormal lactic and pyruvic acid d. bright facies and absent DTRs References* Jones, K.L. (2006). Smith's recognizable patterns of human malformation (6th ed.). Philadelphia: Elsevier Sanders. Saul, Robert, et.al. (1998). Growth references: Third trimester to adulthood. Greenwood Genetic Center. *Additional resources are listed in the slide presentation. Session Outline See handout on following pages. B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 2 of 24

3 How Do I Know You? Let me count the genes Karlene Coleman, RN, MN, CGC Certified Genetic Counselor Children s Healthcare of Atlanta karlene.coleman@choa.org Families eventually want to know.. What Happened? Why did it happen? Will it Happen again? Is it Genetic? Is it Inherited? Is there Treatment? Is there Prenatal Testing? Genetic diseases Chromosomal Single gene Mendelian Inheritance Dominant, Recessive, X-linked Multifactorial The general population risk for a birth defect or genetic disease is 3% or 1/33 births! Cytogenetics G-banding Chromosome Technology Progress Technology Resolution Sample Diagnosis Karyotype Whole Down syndrome (1970 s) Chromosome Large Deletions or duplications (> 4 Mb) Fluorescence in situ ~ 100 kb 22q11.2 syndrome Hybridization (FISH) VCFS (1990 s) Tests a single locus at a time Need Prior knowledge of region Array CGH Flexible, only Submicroscopic (2000 s) limited by probe deletions/duplications spacing (> 1 kb) anywhere in the genome Can test whole-genome simultaneously Slide courtesy of Jennifer Mulle PhD B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 3 of 24

4 Down Syndrome Signs in the Neonate 80% Hypotonia 85% Poor Moro reflex 80% Hyperflexibility of joints 80% Excess skin on back of neck 90% Flat Facial Profile 80% Upslanted palpebral l fissures 60% Anomalous Auricles small, overfolded helix 70% Dysplasia of Pelvis on x-ray 60% Dysplasia of midphalanx of fifth finger 45% Single transverse palmar crease 6 or more of above features are found in 89% of Down syndrome neonates 1:600 live births advanced maternal age effect Down syndrome other features Head Brachycephaly with flat occiput Eyes Speckling of iris (Brushfield spots) 70% refractive errors myopia 45% strabismus Cardiac anomalies in 40% AVC, Endocardial cushion defect Feet Wide gap between toes 1 & 2 Plantar crease between toes 1 & 2 Genitalia Small penis Decreased testicular volume Primary gonadal deficiency is common Palmar & Plantar creases in Down syndrome Single Transverse Palmar Crease Deep plantar furrow & gap between toes 1 and 2 Trisomy 21- Down Syndrome most common chromosomal abnormality in newborns Translocation Down Syndrome Standard Trisomy 21 (95%) Translocation Down Syndrome (4%) Mosaic Down Syndrome (1%) Standard Trisomy 21 Translocation Down Syndrome B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 4 of 24

5 Translocation 21/21 Carrier Parent Mosaicism abnormal cell division resulting in two or more types of cells containing different numbers of chromosomes Down Syndrome Resources Down Syndrome Association of Atlanta National Down Syndrome Congress (NDSC) National Down Syndrome Society (NDSS) Parent to Parent of Georgia click on Genetic Clinics and then Down Syndrome Clinic Trisomy 13 Incomplete development of the Forebrain (holoprosencephaly) Olfactory Optic nerves (micro/anophthalmia, colobomas) Seizures - hypsarrhythmia pattern Microcephaly (> 50%) Sloping forehead Cleft lip and/or palate (60 to 80%) Single umbilical artery (>50%) Trisomy 13 Cutis aplasia of scalp (> 50%) Polydactyly (> 50%) Cardiac (80%): VSD, PDA, ASD Deafness (> 50%) Apnea in early infancy Severe mental retardation Incidence - 1:5000 live births Median age of survival 7 days 91% deceased by 1 year Cutis aplasia Polydactyly B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 5 of 24

6 Trisomy 18 Features > 50% of patients IUGR, polyhydramnios, and single umbilical artery Hypotonia weak cry Prominent occiput Low set malformed ears Short palpebral fissures Short Sternum Clenched Hand with overlapping fingers Rocker Bottom feet Male cryptorchidism Severe mental retardation Monosomy -Turner syndrome (45,X) Short stature, coarctation of the aorta, cystic hygroma/webbed neck, infertility, normal IQ Incidence - 1:1000 live births The only aneuploid that seems unrelated to mother s age Incidence - 1:3000 live births 90 to 95% deceased by 1 year In Neonates: Webbed neck Shield chest with wide spaced nipples Coarctation of Aorta Lymphedema of hands and feet 45,X Turner syndrome New Technologies in Testing - FISH Looks for small specific sections of DNA (30-50 genes) that would be missed by routine chromosome analysis Detects microdeletion syndromes like: 22q11.2 deletion aka velo-cardio-facial synd. aka DiGeorge synd. 7q11 del Williams FISH advantage 24 hour turn around time 22q11.2 deletion, Velo-cardio-facial syndrome, DiGeorge syndrome 22q11.2 Region and FISH Incidence ~1:2000 live births Conotruncal cardiac defects: 76% IAA, Truncus arteriosus, TOF, VSD Abnormal facies 100% (more difficult to assess in African American infants) Thymic aplasia/ hypoplasia: 77% Clefting/ palate abnormalities: 83% Hypoparathyroid - hypocalcemia: 49% 22q11.2 deletion B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 6 of 24

7 22q11.2 deletion, Velo-cardio-facial syndrome, DiGeorge syndrome 90% of cases are sporadic (not inherited) 10% of cases are inherited from mom or dad Parents who have the deletion have a 50% chance of passing it on to every future pregnancy Most parents with the deletion required Special Education in school Facial Features: short and narrow palpebral fissures, long faces, high palates with hypernasal speech History of heart defects or GI problems Facial Features in 22q11.2 deletion Hooded eyelids Short and narrow palpebral fissures Bulbous nose or bifid nasal tip hypoplastic alae nasi Microstomia Developmental & speech delay 22q11.2 deletion - Features in infants Normal ear Typical ear for 22q11.2 deletion: deficient upper helix overfolded helix small ear C-shaped ear 22q11.2 del Asymmetric crying facies Swallowing difficulties FTT 22q11.2 deletion - What to offer families B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 7 of 24

8 Ryan and Jenny Dempster Family Foundation 22q Resources on the Web International 22q Foundation Ryan and Jenny Dempster Family Foundation emory edu/22q Southeastern Center for Excellence in 22q Genetic Conditions and Rare Conditions Support Groups Parent to Parent of Georgia DiGeorge phenotype without 22q11.2 deletion Fish for Williams syndrome Do not rely on FISH results only. 10% of patients with DiGeorge phenotype do NOT have the 22q11.2 deletion They are still DiGeorge and need to be treated accordingly Williams syndrome 7q11 deletion by FISH Contiguous gene deletion syndrome Hemizygosity at the elastin (ELN) locus is thought to explain the supravalvular aortic stenosis (SVAS), hoarse voice and rapidly aged-appearing skin Flanking genes to the 7q11 region are thought to cause the other manifestations Disruptions of (ELN) at 7q11.23 cause the autosomal dominant form of isolated SVAS Williams syndrome Intermittent infantile hypercalcemia Growth retardation IUGR, SGA Cardiovascular anomalies: supravalvular aortic stenosis (SVAS) peripheral pulmonic stenosis (PPS) Mild to moderate mental retardation Outgoing friendly personality Incidence 1:20,000 live births B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 8 of 24

9 Williams syndrome 7q11.23 del Mild prenatal growth deficiency FTT in infancy (70%) Poor linear growth the first four years Mean adult height is below 3rd percentile Williams syndrome 7q11.23 del Periorbital fullness Bitemporal narrowing Short nose Full nasal tip Malar hypoplasia Long philtrum Wide mouth Small jaw IUGR/SGA Prader Willi (PWS) & Angelman (AS) syndromes Prader Willi Syndrome (PWS) Chromosome 15q11-q13 del PWS Obesity (onset 6 months to 6 years), hypotonia, MR, small hands and feet, short stature, almond shaped eyes, narrow bifrontal diameter, hypogonadism Chromosome 15q11-q13 del AS -MR, seizures, short stature, blond hair, hypopigmentation, large mouth, wide spaced teeth, prognathia Neonates present with: Hypotonia - FTT May require ventilator support Hypogonadism in males Incidence - 1:15,000 live births PWS & AS: Need not only 46 chromosomes Need one from each pair from mom and one from dad Chromosome 15q11-q13 Uniparental Disomy UPD: the presence in the karyotype of two copies of a specific chromosome, both inherited from one parent, with no representative of that chromosome from the other parent. Embryonic Trisomy Rescue Angelman syndrome Prader Willi syndrome B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 9 of 24

10 Prader Willi Syndrome 3 etiologies Prader Willi Syndrome Initial Screening Test Sporadic Sporadic Could carry 50% risk for recurrence 70-75% 25-29% < 1% Array-based Comparative Genomic Hybridization Array-based CGH Patient DNA Genomic Clones Patient DNA Genomic Clones NORMAL Loss: ratio < 0.8 Control DNA Only detects unbalanced rearrangements Control DNA Normal: ratio Gain: ratio > 1.2 Pinkel et al., Nat Genet (1998), 20(2): Slide courtesy of Christa Martin, PhD Emory Array Formats and Characteristics Turner synd. (45,X) Normal (46,XX) 47,XXX EmArray 60K: 60,000 oliognucleotides, covers 75 kb whole genome and 400 targeted region. List price: $1,695. EmArray 180K SNP: 180,000 oligos, covers areas of 25 kb whole genome and absence of heterozygosity for UPD and areas of common descent [consanguinity]. List price: $1,995. Array image from UCSF website B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 10 of 24

11 1.65 Mb Heterozygous deletion 16q23.1q23.2 Small (200 kb) Heterozygous deletion of 7q35 Chr 16 Chr. 7 22q11.2 Region and FISH oligo probe coverage on EmArray 3 Mb DGS region FISH probe (~100 kb) used for testing only covers this gene Prevalence ~1:2000 live births EmArray Results - ABNORMAL Inheritance of CNVs by array CGH assays (clinical diagnostics) Trisomy 21 Notice majority of oligos are shifted to the right, outside of the green line Child 21 Chr 21 B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 11 of 24

12 Inheritance of CNVs by array CGH assays (clinical diagnostics) Limitations of Standard array CGH technologies Father Mother Cannot detect low-level mosaicism (<20-30%) Cannot detect balanced translocations Cannot detect structural variants (inversions) Child Limitation: Microarray will not detect Balanced Structural Abnormalities 4p+ and 11q- (This was not detected on prenatal chromosomes) 4pter-p16.1 gain: 8.3Mb 11q23.2-qter loss: 15.6Mb 4p duplication: prominent glabella, depressed nasal bridge, bulbous nose, short neck, low hairline, growth and mental retardation, parents at risk for balance carrier status 11q deletion: Jacobsen syndrome, ocular hypertelorism, large, carp shaped mouth, cardiac defects, ParisTrousseau (neonatal thrombocytopenia) Patient MH: Single ventricle cortriatrium hypoplastic aorta Indications for Microarray Use As an alternative to routine chromosomes or FISH Routine chromosomes abnormal detection rate is 5% Microarray abnormal detection rate is 18 to 20% Assess the size and gene content of unbalanced chromosomal rearrangements To test for cryptic deletions/duplications in individuals with apparently balanced translocations and a clinical phenotype B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 12 of 24

13 Application of high-throughput biological instrumentation design principles: Next generation DNA sequencing ~20,000,000 sequences ~10,000 sequences What to draw? Chromosomes: 4 cc s green top sodium heparin tube (minimum 2 cc s for infants) FISH 1-2 cc s green top sodium heparin tube Chromosomal Microarray 4 cc s in green top sodium heparin tube AND 4 cc s in a purple top EDTA tube (minimum 2cc s in each for infants) Lab Forms: Click on Emory Genetic Lab Click on Forms Test name: EmArray Cyto6000 Oligo Array 2007 J. Craig Venter Decoded a full diploid genome his and James Watson s 1990 Human Genome Project goals included: determine the sequences of the 3 billion chemical base pairs that make up human DNA ***It took 13 years and 500 million dollars It took 3 months and $300,000 each Charting a course for genomic medicine from base pairs to bedside As of September 2012 Whole exome sequencing for $9,000 TAT 15 weeks Goal: to be able to do individual genomes for under $1,000 Eric Green, Mark Guyer & National Human Genome Research Institute (NHGRI) N AT U R E VO L F E B R U A RY B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 13 of 24

14 HGP What are they finding? Chromosome to genes In the 3 billion base pairs there are: 21,000 Protein coding genes 15,000 will be linked to diseases 2,500 are known to cause disease today Testing strategies for Mendelian Diseases: Biochemical testing Gene Sequencing The human genome is made up of 3 billion ( ) bases of DNA The four letters of the DNA alphabet A, C, G, and T are used to carry the instructions ti for making an organism. The order (or sequence) of these letters holds the code for the building blocks (20 amnio acids) used in various combinations to make genes which in turn produce our proteins, for example keratin in hair and hemoglobin. Modes of Inheritance Autosomal: non-sex determining chromosome (one of the first 22 in humans) Autosomal mutations effect males and females equally! Types 1. Autosomal Dominant 2. Autosomal Recessive B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 14 of 24

15 Autosomal Dominant Autosomal Dominant Transmitted from parent to child or can occur as new mutations Affected person has a 50% chance of passing trait Tend to occur in every generation Examples: Achondroplasia Marfan Syndrome Nuerofibromatosis Type I Myotonic Dystrophy Myotonic Dystrophy Congenital: Appears at birth - is most severe Juvenile: Appears after birth and in teen years Adult: Appears in the late 20's to early 40's Late Onset: Appears later after 40's and generally mild Incidence 1:8000 Incidence of the congenital form 1:100,000 Characterized by muscle stiffness and progressive dystrophic changes leading to muscle weakness and atrophy Myotonia is defined as hyperactivity of the muscle cell membrane The problem lies in the inability of the muscles to relax once contracted Genetic Mechanisms of Myotonic Dystrophy (Normal CTG repeat size is 5-34): Caused by an excessive number of CTG trinucleotide repeats of one allele on Chr 19 (q13.2q13.3) Unaffected persons have from 5-34 repeats Congenital Myotonic Dystrophy one allele has over 2000 repeats DNA test ~ $ B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 15 of 24

16 Congenital Myotonic Dystrophy This form is evident prenatally Diminished fetal movements Polyhydramnios Occurs in 50% of offspring of myotonic mothers (never fathers) Affected mother may be minimally affected and often undiagnosed Prevalence 1 in 100,000 (1 in 3,500 in Sweden) Neonatal Signs of Myotonic Dystrophy Diminished cry Poor suck reflexes Severe hypotonia weak muscle tone and floppiness Severe respiratory compromise likely to be ventilator dependent Extensive facial weakness Moms have hypotonic facies SM: 1 month old Hispanic Congenital myotonic dystrophy SM: Congenital myotonic dystrophy Floppy in delivery room Apnea intubated in DR Ventilated for 1 month Hypotonic facies Open mouth Tented upper lip Poor tone Poor movements Test Results: Allele 1: 5 repeats Allele 2: 2400 repeats Hypotonic facies in mom Mental retardation: mom was in 5 th - 11th grades in USA and still does not speak English Myotonic dystrophy Shake hands - affected person will grasp but have difficulty releasing grip Mom s grip and release CHARGE syndrome Colobomas 80-90% iris or retina Heart 75-80% Aortic Valve stenosis, coarctation, IAA, TGA Atresia Choanae 58% Retardation of: Growth (70%) Development 100% Genital hypoplasia in males 75% Ear anomalies and deafness 90% B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 16 of 24

17 CHARGE syndrome: Square face with asymmetry Cleft lip and palate (30%) CHARGE syndrome Ti Triangular Crus Underdeveloped Upper helix Over folded Upper helix Moderate to severe hearing loss CHARGE syndrome Inheritance: usually sporadic however, once it occurs. it is Autosomal Dominant (50% risk for recurrence) in the affected individual Some presentations can be very mild be sure to evaluate parents for subtle physical signs and for hearing impairment CHARGE syndrome Consider CHD7 testing if positive, prenatal testing could be offered to future pregnancies Sequence analysis/mutation scanning of the CHD7 coding region detects mutations in approximately 60% - 65% of individuals with Charge syndrome Cost: $3600 Congenital Central Hypoventilation Syndrome (CCHS) Generalized autonomic nervous system dysfunction/dysregulation (ANSD) Characterized by adequate ventilation while the affected individual is awake and by hypoventilation during sleep Subset with altered neural crest-derived structures (i.e. Hirschsprung) and tumors of neural crest origin including neuroblastoma, ganglioneuroma etc. Can present in newborn, childhood or adulthood. Congenital Central Hypoventilation Syndrome (CCHS) 92% of affected individuals have a PHOX2B polyalanine repeat expansion of repeats 8% of affected individuals need the entire gene sequenced to detect deletions or point mutations ~5% of parents are mosaic for the mutation and have a 50% risk for recurrence in every future pregnancy Autosomal Dominant 50% recurrence risk B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 17 of 24

18 CCHS: Congenital Central Hypoventilation Syndrome 2006 Son born by IVF with mom s egg and dad s sperm Central Hypoventilation Hirschsprung Labile blood pressure Mom had Hirschsprung Disease No issues with respiratory deficiency or anesthesia Mom was mutation positive in blood (with brain spairing) Mom unconvinced about mosaicism and used frozen embryo for next pregnancy CCHS: Congenital Central Hypoventilation Syndrome Second Affected Son Mowat-Wilson Syndrome (MWS) Multiple congenital anomaly/mental retardation syndrome first described by Mowat et al in 1998 Hirschsprung disease Microcephaly Characteristic facial features Congenital Heart Disease Molecular Basis Locus identified on 2q22 All cases thus far have been sporadic 15% - Large deletions 81% - Heterozygous mutation of the ZFHX1B (SIP1) gene 4% Other causes: intermediate deletions and large scale rearrangements Mowat DR et al. (1998) J Med Genet 35: Typical Facial Features - MWS Typical Facial Features - MWS Ocular hypertelorism Medially flared and broad eyebrows Prominent columella Prominent or pointed chin Uplifted earlobes with a central depression Open mouth expression Admitted with Hirschsprung Ocular hypertelorism Medially flared and broad eyebrows Prominent columella Prominent or pointed chin Uplifted earlobes with a central depression Admitted with CHD B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 18 of 24

19 Autosomal Recessive Both parents are carriers Ethnic background is significant Increases with consanguinity Usually not seen in every generation Examples: Sickle Cell Cystic Fibrosis Spinal Muscular Atrophy Autosomal Recessive Are you a carrier of a recessive disorder? Spinal Muscular Atrophy 2 nd most common AR disorder after CF Type 1: Werdnig-Hoffman 7/100,000 live births Autosomal Recessive Hypotonia Facial weakness minimal DTRs decreased or absent Tongue fasciculations SMN1 gene mutation degeneration or loss of motor neurons in the anterior horns of the spinal cord Types II and III - later ages of onset NBS: Prevention! Untreated and Treated PKU Occurring in ~1 in 10,000 babies born in the U. S Can cause mental retardation, organ damage, and unusual posture if untreated Treatment of PKU is the elimination of phenylalanine from the diet B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 19 of 24

20 Newborn Screening:Tandem Mass Spectrometry [TMS] Newborn Screening: It s Not Just the PKU Test! Amino Acid Profile Acylcarnitine Profile Organic Acids (parital) NBS: HRSA/ACMG/MOD/AAP: 2004 Genetics in Medicine. Vol 8. May disorders on a Uniform Panel 9 Organic Acidemias 5 Fatty Acid Oxidation Defects 6 Amino Acidopathies 3 Hemoglobinopathies 6 Others: CH, CAH, Galactosemia, Cystic Fibrosis, Hearing 25 additional Reportable Disorders found by TMS Georgia Newborn Screening State Specific Web Sites Have Valuable Information Modes of Inheritance Cont X-Linked Dominant in Males X-Linked- mutations in genes on the X chromosome X-linked dominant fathers cannot pass X-linked traits to their sons Can be lethal in males X-linked recessive fathers cannot pass X-linked traits to their sons Males are more frequently affected than females Rarely have affected females B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 20 of 24

21 X-Linked Dominant in Females Example of X-Linked Dominant Rett Syndrome MECP2 gene A disorder of brain development almost exclusively in girls Males: severe encephalopathy and die prenatally or by 2 yrs Female Neonates some are placid, poor suck, weak cry Females: Normal up to 6-18 months then regression of speech and motor function especially purposeful hand movements X-Linked Dominant - Fragile X expansion of a CGG tandem repeat in the FMR1 gene Males: Average IQ < 50 ADHD/ Autism spectrum Post pubertal macroorchidism Large ears & dysmorphisms Avoidance of eye contact Females (milder): ADD Learning disabilities Personality disorders Premature ovarian failure (20%) Fragile X Mental Retardation 1 (FMR1) CpG Transcription Island Translation (CGG)n 5 3 ~44 repeats Common ~45-54 repeats Intermediate ~ repeats > 200 repeats, methylated Premutation Full mutation Male Female 1/25 1/12 1/800 1/250 1/4000 1/4000 X-Linked Recessive in Males X-Linked Recessive in Females B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 21 of 24

22 Example of X-Linked Recessive Hemophilia A (Xq28)- decreased production of Factor VIII, required for normal clotting Example of X-Linked Recessive The Tsar in Waiting: Alexis Duchenne muscular dystrophy (Xp21.2)- decreased production of dystrophin, required for normal muscle activity Females are rarely affected by these forms of muscular dystrophy Copyright restrictions may apply. Multifactorial conditions: Caused by a combination of genes and environmental effects Isolated Heart defects Isolated Cleft lip +/- palate Isolated Spina bifida Multifactorial Conditions Cleft Lip/ Cleft Palate Babies can be born with both cleft lip and cleft palate Males are affected more frequently than females. Occurs more frequently in Asians, American-Indians, and African Americans B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 22 of 24

23 Multifactorial Conditions Spina Bifida is the most common of a group of birth defects called neural tube defects (NTDs) affects the backbone and, sometimes, the spinal cord B vitamin folic acid- can prevent some neural tube defects (including spina bifida) Prevention - Folic Acid Revolution All women of reproductive age need 400 micrograms of folic acid daily Women who have had a neural tube defect need 4000 micrograms while planning and during a pregnancy 4000 micrograms of folic acid a day from folic acid only pills --needs a prescription Folic acid also thought to be helpful for cleft lip and or palate and congenital heart defects Prevention Folic Acid Need to start at least 3 months prior to conception for best effect Teratogens and Environmental Diabetic Embryopathy: Caudal regression clubbed foot CHD Pre-hallucal polydactyly Maternal PKU Powerful Teratogen Maternal PKU Powerful Teratogen Microcephaly, Coarc Aorta, Multiple VSDs Microcephaly, Coarc Aorta, Multiple VSDs B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 23 of 24

24 Environmental causes of Birth Defects Amniotic Bands Oblique facial cleft Resources on the Web On-line Mendelian Inheritance in Man (OMIM) Or Google OMIM Genetic Conditions and Rare Conditions Support Groups For updated summaries for specific genetic diseases click on Gene Reviews box at top of home page and then type the disease name in the search window Emory Genetics Laboratory for tests and forms Other states will have similar labs and genetic services B3: GENERAL GENETICS & NEW TECHNOLOGIES IN TESTING Page 24 of 24