Pediatric Genetics & Genomics
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- Pediatric genetics specialists Dr. Leah Burke and Dr. Mark Korson presented on genetic testing modalities and biochemical tests that can help identify underlying genetic or metabolic disorders. - They reviewed various genetic testing options including karyotyping, FISH, microarrays, and sequencing and discussed their strengths and limitations. Variants of uncertain significance were highlighted as a challenge. - Clinical findings that should prompt referral for further genetic evaluation were discussed. These "red flags" included individuals who are too tall/short, develop too early/late, have too many/few features, or have features that are too different. - An initial genetics evaluation was outlined including obtaining a three generation family history, physical exam
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Pediatric Genetics & Genomics
- 1. Pediatric Genetics and Genomics April 28, 2020 Lab Testing and Genetic & Metabolic Disease: Spotting the "Red Flags" 1 Leah Burke, MD University of Vermont Mark Korson, MD VMP Genetics, LLC
- 2. Get the Most Out of Your Experience Use the Q&A Button to submit questions during today’s session Recording and slides will be sent by email For further information, contact WeitzmanLearning@chc1.com 2
- 3. Founding year: 1972 Hubs/Locations: 15/210 Patients per year: 100,000 The Weitzman Institute is a program of 3
- 4. 4 The Weitzman Instituteworks to improve primary care and its delivery to medically underserved and special populationsthrough research, innovation, and the education and training of health professionals. 4Genetics | 2/18/204
- 5. New England Regional Genetics Network The NERGN project is supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under grant number UH7MC30778; New England Regional Genetics Network; total award amount: 1.5 million; 100% from governmental sources. This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government. 5
- 6. CME Credits Available CME credits available to live webinar participants only A brief survey will be sent after this session to those who registered and attended this webinar CME certificate will be sent to participants who complete the survey American Academy Family Physicians (AAFP) 6
- 8. Today’s Presenters Dr. Leah W. Burke, MD Dr. Mark Korson, MD 8
- 9. Goals • Review the genetic and genomic testing modalities • Identify the clinical and family history findings that raise a concern for a genetic disorder • Review how simple biochemical tests that can determine the competence of human metabolism • Describe a few findings on routine biochemical testing that can increase suspicion about an underlying metabolic disease
- 10. Genetic Testing: Screening vs. Diagnostic • Testing done on a particular population • Individuals are asymptomatic • Not designed to diagnose, simply to identify individuals at a higher risk • May lead to diagnostic tests • Testing done on individuals • Individuals often symptomatic • Individuals may have had a positive screening test • May lead to treatment options
- 11. Diagnostic Genetic Testing Karyotype FISH Image Fluorescence In Situ Hybridization Microarray Jax.com
- 13. Karyotype
- 14. Karyotype Compare the Karyotype to published Idiograms 2q34 2q10 2p24
- 15. Diagnostic Genetic Testing Karyotype FISH Image Fluorescence In Situ Hybridization Microarray Jax.com
- 16. FISH: Fluorescence in situ Hybridization
- 17. Diagnostic Genetic Testing Karyotype FISH Image Fluorescence In Situ Hybridization Microarray Jax.com
- 18. What’s in a name? A test by any other name… • Microarray • Chromosomal microarray • Whole genome microarray • Comparative Genomic Hybridization (CGH) • Array CGH Function is to determine copy number variants
- 19. Microarray Duplication in patient Deletion in patient Normal copy number
- 20. 20 Karyotype Individual FISH test Microarray Can detect whole chromosome differences, translocations, and large deletions or duplications Only looks at specific areas for deletions or duplications Can detect very small duplications or deletions
- 23. • A massively parallel sequencing technology in which millions of overlapping “reads” of DNA sequences are done simultaneously • Creates an enormous amount of data to be analyzed • Can detect single gene mutations including nonsense, missense, splice-site, and frame-shift mutations 23 Next Generation Sequencing
- 24. 24
- 25. 25
- 26. Whole Exome Sequencing (WES) • Now being offered clinically • Parallel sequencing of at least 98% of the coding sequences Whole Genome Sequencing (WGS) • Parallel sequencing of the coding and non-coding sequences • Some conditions are caused by DNA changes outside the “gene” 26 Both are being considered in rapid testing of sick newborns in the NICU and other places
- 27. Lots of data…What happens next? 27
- 28. 28 Variants of Uncertain Significance: The Dreaded VUS
- 29. • With whole genome sequencing or whole exome sequencing, the chance of VUS is even greater than with microarray testing • The reading of the variants can be different between different labs and over time 29 Variants of Uncertain Significance: The Dreaded VUS
- 30. So when should you refer for a genetics/metabolism evaluation? 30
- 31. REMEMBER THE RULE OF “TWO/TOO” (when asking questions) • TOO tall • TOO short • TOO early • TOO many • TOO young • TOO different • TWO tumors • TWO generations • TWO in the family • TWO birth defects
- 32. Let’s start with the Too’s • TOO tall • TOO short • TOO early • TOO many • TOO young • TOO different 32
- 35. Too tall • Cerebral gigantism (Sotos syndrome) • Marfan syndrome • Beckwith-Weidemann syndrome • Homocystinuria • XYY males • Other syndromes
- 37. • Prenatal onset overgrowth • Cerebral gigantism • Dolichocephaly • Frontal bossing, prognathism, pointed chin, downslating palpebral fissures • High-arched palate • Developmental delay, poor coordination, behavioral problems, autism, seizures • Ventriculomegaly, absent corpus callosum, persistent cavum septum pellucidum Sotos syndrome
- 39. Marfan Syndrome • Tall stature with long bone overgrowth • Long narrow face • High-arched palate • Subluxation of lenses • Spontaneous pneumothoraces • Arachnodactyly • Aortic root dilation and dissection • Mitral regurgitation • Scoliosis • Pectus deformities • Joint hypermobility • Striae dystrophica • Recurrent hernias Usually due to a FBN1 (fibrillin 1) mutation Also consider TGFBR1 and TGFBR2
- 41. Beckwith-Wiedemann • LGA babies without maternal diabetes • Macroglossia • Hemi-hypertrophy • Ear creases and or posterior pits • Umbilical hernia or omphalocele • Wilms tumor
- 42. Too short • History of Growth deficiency – Onset • Prenatal – intrauterine growth retardation • Postnatal – Growth maturation • Normal • Delayed – Proportional • Proportions are normal • Malproportion
- 45. Achondroplasia • Short-limb dwarfism – rhizomelic shortening • Macrocephaly with frontal bossing • Midface hypoplasia • Foramen magnum stenosis • Upper airway obstruction • Kyphosis and lumbar lordosis • Trident hand • Limited elbow extension • Generalized joint hypermobility • Bowing of legs • Conductive hearing loss • Delayed motor development • Occasional hydrocephalus • Mutations in FGFR3 gene (80% de novo)
- 46. Too many 46
- 47. Too many 47
- 48. Skin Manifestations: Subcutaneous Neurofibromas
- 49. Too different 49
- 50. Eyes Too close Normal Too wide Short Normal Long Upslanting Nl Downslanting Ears
- 51. Too different • Developmental delay • Autism 51
- 52. Initial Genetics Evaluation: First Tier • Three generation family history • Medical history for clues about birth/environmental causes • Physical evaluation for signs of underlying syndromes – Targeted testing for a specific syndrome – Metabolic and/or mitochondrial testing if indicated • Chromosomal microarray • Fragile X DNA testing
- 53. Fragile X physical features • Macrocephaly • Long face with prominent jaw and long ears • Joint hypermobility • May not have any striking features
- 54. Fragile X Syndrome • Caused by a change in the FMR1 gene located on the X chromosome • A full mutation is expressed in 100% of males and 50% of females • Intellectual disability is a major feature in affected males • Must be tested for with a specific test that determines the repeat size
- 55. Initial Genetics Evaluation: First Tier • Three generation family history • Medical history for clues about birth/environmental causes • Physical evaluation for signs of underlying syndromes – Targeted testing for a specific syndrome – Metabolic and/or mitochondrial testing if indicated • Chromosomal microarray • Fragile X DNA testing
- 56. Chromosomal Microarray An important part of the First Tier • Numerous pathogenic copy number variants (CNVs) have been identified in the etiology of autism • Yield is thought to be about 10% • Several “hot spots” or recurrent CNVs have been identified • Often present in unaffected parents – variable penetrance
- 57. Case • 18 month old girl referred to genetics for gross motor delays • Additional features – Small VSD – Epicanthal folds and puffy eyelids – Upturned nose and wide mouth – Difficulty gaining weight • Facial features reminiscent of Williams syndrome but didn’t completely fit • Did the first tier of testing 57
- 58. Case • Seen again at 5 ½ years and proposed doing exome sequencing • Received approval from insurance, but parents decided to wait • At 6 years of age, she was diagnosed with celiac disease • Parents proceeded with testing • A pathogenic variant was found in SETD5 58
- 59. SETD5 • Associated with an autosomal dominant neurodevelopmental syndrome • Found on the short arm of chromosome 3 • Deletions in this area have been known to cause a neurodevelopmental syndrome 59
- 61. REMEMBER THE RULE OF “TWO/TOO” (when asking questions) • TOO tall • TOO short • TOO early • TOO many • TOO young • TOO different • TWO tumors • TWO generations • TWO in the family • TWO birth defects
- 62. The Two’s 62
- 63. • Chief complaint • Family History, if available: – Include 3 generations if available – Designate how each person is related – Include developmental history – Do not limit to symptoms found in patient – Include causes of death, esp. in early deaths – Include miscarriages & early infant deaths – Include consanguinity and ethnicity WHAT THE PCP SHOULD PROVIDE WITH THE REFERRAL
- 64. (35) Breast Cancer @ 63 died @ 67 - heart disease Breast Cancer @ 58 post-menopausal died at 63 - metastases Breast cancer @ 80 died @ 83 Irish, English, ScottishIrish, German (60) (87) (62) Prostate cancer 70’s (84) (62)
- 65. Russian Jewish (35) bre ca @ 42 died @ 48 bre ca @ 45 died @ 52 bil bre ca @ 45, 52 died @ 80
- 66. • SC – some concerns re: diseases in family “Do you have any questions about diseases or conditions that run in your family?” • R – reproduction problems “Have there been any problems with pregnancy, infertility, or birth defects in your family?” • E – early disease, death, or disability “Have any members of your family become sick or died at an early age?” • E – ethnicity “How would you describe your ancestry?” OR “What countries do your families originate from? • N – non-genetic factors “Are there any other nonmedical conditions that run in your family?” FAMILY HISTORY SCREEN MNEMONIC
- 68. Let’s take a walk to the Chemistry Lab…
- 69. BASIC LAB TESTING: THE THEORY
- 70. • Can help assess the competence of metabolism of: • Protein • Carbohydrates • Fat BASIC LAB TESTING: THE THEORY
- 71. • Can help assess the competence of metabolism of: • Protein • Carbohydrates • Fat BASIC LAB TESTING: THE THEORY
- 72. - C - N -- ANATOMY OF AN AMINO ACID
- 73. - C - N -- UREA CYCLE
- 74. - C - -- ORGANIC ACID
- 78. AMINO ACIDS CHANGE Krebs cycle Urea cycle ORGANIC ACIDS NH3 ATPELECTRON TRANSPORT CHAIN PROTEIN DEGRADATION TESTING - Ammonia - Blood gases - Electrolytes - Anion gap Organic acidemia Urea cycle disorder
- 79. BLOOD GAS MEASUREMENT pH pCO2 HCO3
- 80. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Blood pH=7.4 Low pH acidic High pH alkalotic Blood HCO3=24 Low HCO3 acidic High HCO3 alkalotic
- 81. TACHYPNEA A WAY TO BLOW OFF ACID pH pCO2 HCO3 H+ + HCO3 - H2CO3 H2O + CO2
- 82. TACHYPNEA A WAY TO BLOW OFF ACID pH pCO2 HCO3 Blood pH=7.4 Low pH acidic High pH alkalotic Blood pCO2=40 Low pCO2 rapid breathing High pCO2 slower breathing Blood HCO3=24 Low HCO3 acidic High HCO3 alkalotic
- 83. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW Urea cycle disorders HIGH LOW LOW
- 84. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW 1° METABOLIC ACIDOSIS
- 85. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW 1° METABOLIC ACIDOSIS
- 86. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW 1° METABOLIC ACIDOSIS 2° RESPIRATORY ALKALOSIS
- 87. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW 1° METABOLIC ACIDOSIS 2° RESPIRATORY ALKALOSIS
- 88. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW Urea cycle disorders HIGH LOW LOW
- 89. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Urea cycle disorders HIGH LOW LOW 2° RESPIRATORY ALKALOSIS
- 90. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Urea cycle disorders HIGH LOW LOW 2° RESPIRATORY ALKALOSIS
- 91. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Urea cycle disorders HIGH LOW LOW 2° RESPIRATORY ALKALOSIS 1° METABOLIC ACIDOSIS
- 92. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Urea cycle disorders HIGH LOW LOW 1° RESPIRATORY ALKALOSIS 2° METABOLIC ACIDOSIS THIS SLIDE HAS BEEN UPDATED POST PRODUCTION. THE INFORMATION ON THIS SLIDE IS CORRECT. THE INFORMATION ON THE SLIDE SHOWN ON THE RECORDING IS INCORRECT AS POINTED OUT BY DR. KORSON
- 93. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW Urea cycle disorders HIGH LOW LOW
- 94. A CASE OF VOMITING & LETHARGY A 10 month old girl presents to the ER with her second bout of vomiting and dehydration. The first resolved with IV fluids. She is now lethargic and tachypneic. Her blood gases show- pH=7.54, pCO2=16, HCO3=17. Electrolytes reveal Na=142, K=3.1, Cl=107, HCO3=18. Glucose measures 62 mg/dL.
- 95. QUESTION Which ONE of the following choices regarding the patient’s presentation is the most diagnostically helpful? A. The glucose level B. This is the second episode of vomiting/dehydration C. The respiratory alkalosis D. The metabolic acidosis E. The patient’s lethargy
- 96. QUESTION Which ONE of the following choices regarding the patient’s presentation is the most diagnostically helpful? A. The glucose level B. This is the second episode of vomiting/dehydration C. The respiratory alkalosis D. The metabolic acidosis E. The patient’s lethargy
- 97. RESPIRATORY ALKALOSIS Hyperventilation Medications/drugs Pain Fever Intracranial: • Malformations • Trauma Hyperammonemia Causes
- 98. THE ANION GAP Difference between measured anions and cations in the blood Definition Calculation Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (105 + 25) Anion gap = 10 Normal anion gap = 10-15
- 99. NON-ANION GAP ACIDOSIS Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (115 + 10) Anion gap = 15 Bicarbonate loss (urine or stool) HIGH NORMAL LOW
- 100. ANION GAP ACIDOSIS Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (105 + 10) Anion gap = 25 Anion accumulation NORMAL HIGH LOW
- 101. AMINO ACIDS CHANGE Krebs cycle Urea cycle ORGANIC ACIDS NH3 ATPELECTRON TRANSPORT CHAIN PROTEIN DEGRADATION DEFECTS: Ammonia Blood gases Electrolytes Anion gap Organic acidemia Urea cycle disorder
- 102. • Can help assess the competence of metabolism of: • Protein • Carbohydrates • Fat BASIC LAB TESTING: THE THEORY
- 105. CARBOHYDRATE CATABOLISM GLYCOGEN STORAGE DISEASE LACTATE PYRUVATE GLUCOSE GLUCONEOGENESIS GLYCOGEN
- 108. CARBOHYDRATE CATABOLISM TESTING - Glucose - Lactate LACTATE PYRUVATE GLUCOSE GLUCONEOGENESIS GLYCOGEN
- 109. • Can help assess the competence of metabolism of: • Protein • Carbohydrates • Fat BASIC LAB TESTING: THE THEORY
- 110. Krebs cycle ATPELECTRON TRANSPORT CHAIN FATTY ACID CATABOLISM LIVER FATTY ACIDS KETONESACETYL CoA Four-step oxidative cycle
- 112. Krebs cycle ATPELECTRON TRANSPORT CHAIN FATTY ACID OXIDATION DEFECTSFATTY ACIDS KETONESACETYL CoA Four-step oxidative cycle
- 113. Krebs cycle ATPELECTRON TRANSPORT CHAIN FATTY ACID OXIDATION TESTINGFATTY ACIDS KETONESACETYL CoA Four-step oxidative cycle
- 114. Krebs cycle ATPELECTRON TRANSPORT CHAIN FATTY ACID OXIDATION TESTING - Ketones FATTY ACIDS KETONESACETYL CoA Four-step oxidative cycle
- 115. • Aketosis or hypoketosis is always an abnormal response to hypoglycemia (or even very prolonged fasting) • Exception – newborns HYPOGLYCEMIA
- 116. • Routine laboratory testing can be a good indicator for assessing basic intermediary metabolism: • Abnormalities might suggest an underlying acute metabolic disorder SUMMARY • Blood gases • Electrolytes, bicarb (anion gap) • Ammonia • Glucose • Lactate • Urinalysis
- 117. WHICH IS WHICH? Which set of lab results most likely correlates with diarrhea and which with a metabolic disorder? A CASE 1 – diarrhea CASE 2 – metabolic disorder B CASE 1 – metabolic disorder CASE 2 – diarrhea ANALYTE CASE 1 CASE 2 NORMALS Sodium 141 135 133–146 Potassium 5 5 3.7-5.9 Chloride 116 103 98-107 Bicarbonate 10 10 21-31 Anion gap 15 22 8-15 (without K)
- 118. WHICH IS WHICH? Which set of lab results most likely correlates with diarrhea and which with a metabolic disorder? A CASE 1 – diarrhea CASE 2 – metabolic disorder B CASE 1 – metabolic disorder CASE 2 – diarrhea ANALYTE CASE 1 CASE 2 NORMALS Sodium 141 135 133–146 Potassium 5 5 3.7-5.9 Chloride 116 103 98-107 Bicarbonate 10 10 21-31 Anion gap 15 22 8-15 (without K)
- 119. NON-ANION GAP ACIDOSIS Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (115 + 10) Anion gap = 15 Bicarbonate loss (urine or stool) HIGH NORMAL LOW
- 120. ANION GAP ACIDOSIS Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (105 + 10) Anion gap = 25 Anion accumulation NORMAL HIGH LOW
- 121. THE INFANT WITH LIVER DISEASE A 6-month old infant male, product of a healthy pregnancy/labor/delivery, was found to have a distended belly at 3 months. By that time, he had lost 1 kg of weight and was failing to thrive. He continues to feed every 3-4 hours day and night. The liver was noted to be enlarged at 5 months of age. He was evaluated in the ED shortly after that for fever and upper respiratory symptoms.
- 122. THE INFANT WITH LIVER DISEASE Lab tests: • Glucose=39 mg/dL • Mild metabolic acidosis: HCO3=15 • ALT=118, AST=274 • Other liver functions normal • Lactate=3.6 mmol/L (NL<2.2) • Urinalysis: pH=6.5 Based on these clinical/lab data, this patient has liver disease. Which other organ are you worried about? A. Brain B. Kidneys C. Distal extremities D. Heart E. Muscle
- 123. THE INFANT WITH LIVER DISEASE Lab tests: • Glucose=39 mg/dL • Mild metabolic acidosis: HCO3=15 • ALT=118, AST=274 • Other liver functions normal • Lactate=3.6 mmol/L (NL<2.2) • Urinalysis: pH=6.5 Based on these clinical/lab data, this patient has liver disease. Which other organ are you worried about? A. Brain B. Kidneys C. Distal extremities D. Heart E. Muscle
- 124. May be associated with: • Pan-liver dysfunction • Cholestasis • Just hepatomegaly Often associated with renal tubular dysfunction (renal Fanconi syndrome) METABOLIC LIVER DISEASE
- 125. A CASE OF HYPOGLYCEMIA A 2 ½ year old boy develops a cough and cold symptoms. His PCP diagnoses a pharyngitis; the patient takes only smaller volumes than usual. On the third day, he is pale and difficult to rouse. He is rushed to the ED and has a seizure in the car. His blood glucose measures 25 mg/dL. Blood gases – pH=7.29, pCO2=31, HCO3=15. Electrolytes measure Na=131, K=4.4, Cl=99. His urinalysis shows - pH=5.0, no glucose or protein, and 1+ ketones.
- 126. QUESTION Which ONE of the following choices regarding the patient’s presentation is the most diagnostically helpful? A. Hypoglycemia B. Metabolic acidosis C. Hypoglycemia with seizure D. Hypoglycemia with 1+ urine ketones E. Hypoglycemia, hyponatremia, with seizures
- 127. QUESTION Which ONE of the following choices regarding the patient’s presentation is the most diagnostically helpful? A. Hypoglycemia B. Metabolic acidosis C. Hypoglycemia with seizure D. Hypoglycemia with 1+ urine ketones E. Hypoglycemia, hyponatremia, with seizures
- 129. HYPOKETOTIC HYPOGLYCEMIA FAT FATTY ACIDS KETONES HIGH Insulin State
- 130. HYPOKETOTIC HYPOGLYCEMIA HIGH Insulin State • Insulin tumor • Infant of DM mother • Beckwith-Wiedemann syndrome • Iatrogenic
- 131. HYPOKETOTIC HYPOGLYCEMIA FAT FATTY ACIDS KETONES LOW Insulin State
- 132. HYPOKETOTIC HYPOGLYCEMIA LOW Insulin State • Fatty acid oxidation defect • Glycogen storage disease type I
- 133. • Aketosis or hypoketosis is always an abnormal response to hypoglycemia (or even very prolonged fasting) • Exception – newborns HYPOGLYCEMIA
- 134. THE CRITICALLY ILL INFANT A male is the 5th child of non-consanguineous parents following a normal pregnancy and delivery. Within 12 hours, he developed respiratory distress and lethargy, requiring intubation and ventilation. Blood gases showed: pH=7.21, pCO2=10, HCO3=4. Electrolytes: Na=137, K=4.9, Cl=105, measured HCO3=4. Glucose=44 mg/dL. The patient was dehydrated; lactate measured 21 mmol/L (NL<2.2) but persisted despite rehydration. Ammonia=105 μmol/L. Urinalysis: ketones=3+.
- 135. QUESTION The most likely reason for the high lactic acid level in this patient is dehydration leading to poor perfusion? A. True B. False
- 136. QUESTION The most likely reason for the high lactic acid level in this patient is dehydration leading to poor perfusion? A. True B. False
- 137. THE CRITICALLY ILL INFANT A male is the 5th child of non-consanguineous parents following a normal pregnancy and delivery. Within 12 hours, he developed respiratory distress and lethargy, requiring intubation and ventilation. Blood gases showed: pH=7.21, pCO2=10, HCO3=4. Electrolytes: Na=137, K=4.9, Cl=105, measured HCO3=4. Glucose=44 mg/dL. The patient was dehydrated; lactate measured 21 mmol/L (NL<2.2) but persisted despite rehydration. Ammonia=105 μmol/L. Urinalysis: ketones=3+.
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