FEVR. Current Opinion in Genetics & Development 2007;17:1 11 9/2/2014

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1 Experimental/Investigational/Unproven? Chromosomal Microarray Analysis: A Report from the Clinical Trenches David J. Aughton, MD, FAAP, FACMG Division of Genetics, Department of Pediatrics Beaumont Health System, Royal Oak Beaumont Children s Hospital, Royal Oak Current Opinion in Genetics & Development 2007;17:1 11 The clinical implementation of array comparative genomic hybridization has revolutionized the diagnosis of patients with syndromic or nonsyndromic mental retardation. Pawel Stankiewicz and Arthur L. Beaudet Just another typical day in the Genetics Clinic... initial genetic evaluation: 13 Apr 99 age 23 months presented for evaluation of histories of developmental delay ocular findings suggestive of familial exudative vitreoretinopathy (FEVR) FEVR retinopathy similar to ROP [incomplete development of the retinal vasculature] abrupt cessation of peripheral blood vessels in a scalloped pattern at the temporal equator dilated retinal vessels peripheral neovascularization with adjacent preretinal hemorrhage May evolve into fibrovascular scar ectopia of the macula (50%) strabismus (common) Traboulsi EI: A Compendium of Inherited Disorders and the Eye. Oxford University Press, 2006:66 67 Online Mendelian Inheritance in Man FEVR extreme variability of expression autosomal dominant (completely penetrant) EVR1 11q14.2 FZD4 EVR3* 11p13 p12 EVR4 (also autosomal recessive) 11q13.2 LRP5 EVR5* 7q31.31 TSPAN12 *not yet identified in 1999 Traboulsi EI: A Compendium of Inherited Disorders and the Eye. Oxford University Press, 2006:66 67 Online Mendelian Inheritance in Man 1

2 X linked recessive EVR2 Xp11.3 NDP FEVR allelic with Norrie disease Traboulsi EI: A Compendium of Inherited Disorders and the Eye. Oxford University Press, 2006:66 67 Online Mendelian Inheritance in Man Norrie Disease characterized by greyish yellow fibrovascular masses (pseudogliomas) secondary to retinal vascular dysgenesis and detachment congenital blindness (almost always present) developmental delay/intellectual disability, behavioral abnormalities, or psychotic like features (in 30% to 50% of affected males) sensorineural hearing loss (in the majority of affected males) occasional expression in female heterozygotes non random X chromosome inactivation X/autosome translocation the most severe of the NDP related retinopathies Sims KB. NDP Related Retinopathies Jul 30 [Updated 2009 Jul 23]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; Available from: History prenatal history: noncontributory perinatal history: noncontributory postnatal history age 4 m: congenital inturning of the eyes ophthalmologic examination ocular findings suggestive of FEVR age 9 m: developmental delay neurological evaluation 46,XX (20/20 leukocytes) family history: normal parental ophthalmologic examinations physical examination short stature (acquired) absolute microcephaly without relative microcephaly (acquired) blonde patch of hair near the vertex (reportedly congenital) asymmetric dental arch two small hyperpigmented macules (CLMs versus nevi) initial impression Norrie disease (probable) coincidental joint occurrence of monogenic/nonsyndromic FEVR with isolated developmental delay idiopathic/multifactorial chromosomal mosaicism fragile X syndrome other Case 1: Maddie H. initial recommendation: NDP sequencing negative (11 Oct 99) subsequent recommendation: muscle and skin biopsies suggested to the family prior to the initial Genetics Clinic visit offered by me ultimately not done 2

3 follow up genetic evaluation: 21 Dec 00 age 3 8/12 years differential diagnosis syndromic joint occurrence of FEVR and developmental delay Norrie disease (unlikely but not excluded) contiguous gene syndrome/submicroscopic deletion involving one of the several non NDP loci associated with FEVR (e. g.,?del[11][q13q23] [see McK *133780]) (possible but not today amenable to further investigation via clinically available methods) osteoporosis pseudoglioma syndrome mitochondrial disorder (improbable) mosaicism coincidental joint occurrence of isolated FEVR and syndromic developmental delay fragile X syndrome ish del(22q) metabolic disorders other FISH studies of 22q11.2 normal molecular fragile X analysis normal lactate 1.4 mmol/l (WNL) pyruvate 0.09 mmol/l (equivocally elevated) complete metabolic screen essentially normal complete skeletal survey mild hypoplasia of the right first rib audiologic examination retracted tympanic membranes AU hearing loss not excluded AD NCV normal EMG mildly abnormal due to the presence of denervation skin and muscle biopsies revisited neither recommended nor done 10 Feb 04: additional tests ordered but never done methylation studies of chromosome 15 for possible Angelman syndrome 7 dehydrocholesterol assay for possible Smith Lemli Opitz syndrome carbohydrate deficient transferrin for possible congenital disorder of glycosylation follow up genetic evaluation: 17 May 2006 age 9 1/12 years differential diagnosis syndromic joint occurrence of FEVR and developmental delay submicroscopic chromosomal aneuploidy contiguous gene syndrome involving one loci known to be associated with FEVR mosaicism inborn errors of metabolism (unlikely) RECOMMENDATION: CMA CMA Kleberg Cytogenetics Laboratory (Baylor College of Medicine [Houston, Texas]), 17 May 2006 version 5 bacterial artificial chromosome (BAC) based 853 BACs 75 genomic disorders CMA ish del(11)(q14.2q14.2)(rp11 720D4 ) >4.3 Mb deletion detected by CMA confirmed by FISH and partial karyotype FZD4 maps to 11q14.2 I rendered a diagnosis of the 11q deletion syndrome in Maddie s case and considered her to have a contiguous gene syndrome 3

4 initial genetic evaluation: 18 Jun 96 age 14 6/12 years presented for evaluation of short stature History prenatal history: IUGR perinatal history: birth weight and length each < 2 SD postnatal history multiple congenital anomalies atrial septal defect bifid uvula, submucous cleft palate, and velopharyngeal incompetence apparently transient intermittent conductive hearing loss also inguinal hernia, delayed bone age, etc. 46,XY (20/20 cultured skin fibroblasts) in 1987 mild developmental delay family history: atrial septal defect (brother) physical examination short stature with slender habitus absolute and relative microcephaly long and somewhat triangular facies relatively small midface and lower face broad nasal root (not hemicylindrical, however) short philtrum relatively large pinnae gracile hands and feet high pitched voice initial impression velocardiofacial syndrome (probable) 22q11.2 microdeletion syndrome less likely members of the differential diagnosis Russell Silver syndrome fragile X syndrome Dubowitz syndrome other Case 2: Nick D. initial recommendations: FISH studies of 22q11.2 (DGCR probe): negative 46,XY (46/46 leukocytes, 500 band level) visible 22q deletion initially suspected but ultimately dismissed molecular fragile X analysis (Southern blot): negative subsequent recommendation: follow up visit three years thereafter (i. e., ca. June 1999) offered participation in NIH research studies into novel causes of multiple congenital anomalies (not accepted) submicroscopic chromosomal abnormalities uniparental disomy Case 2: Nick D. lost to follow up until May : onset of progressive hearing loss AU balance problems ringing in the ears otolaryngologic evaluation in April 2005 brain MRI, 13 Apr 05: vestibular schwannomata AU diagnostic of type 2 neurofibromatosis (NF2) short stature, developmental delay, and Nick s other anomalies not typical of NF2 follow up Genetics Clinic visit recommended deferred during acute otolaryngologic evaluation/management 4

5 Case 2: Nick D. July 2006: offered further genetic testing NF2 sequencing and deletion/duplication analysis ($500) or CMA ($1500) family elects to pursue CMA CMA Kleberg Cytogenetics Laboratory, 7 Aug 2006 version 5 BAC based 853 BACs 75 genomic disorders (including NF2) CMA arr cgh 22q12.1(RP11 90D17, RP11 113O3)x1.ish 22q12.1(RP11 113O3x1) loss in copy number (deletion) in the NF2 region of 22q detected with two clones confirmed by FISH I rendered a clinical diagnosis of NF2 in Nick s case and considered it probable that his other findings owed to an underlying contiguous gene syndrome parental FISH studies (conducted on a research basis through Baylor): normal/negative evaluation of contiguous genes offered (declined) Sep 12 (prompted by seeing another patient with a similar presentation): offered SNP CMA (declined) 22q11.2 NF2 22q Case 3. Jon B. initial WBH genetic evaluation: 28 Aug 12 age 10 11/12 years presented for transfer of care to Beaumont Case 3. Jon B (age 6 years): neurological evaluation of developmental delay (University of Michigan) routine chromosome analysis, 13 May 08: 46,XY 44K oligonucleotide CMA, 13 May 08: 1.4 Mb deletion at 1q21.1 ultimately found to be of paternal origin 1.8 Mb deletion at 22q12.22 de novo removes both NF2 and CHEK2» abnormal function of CHEK2 causes Li Fraumeni syndrome 5

6 Case 3. Jon B (7 years): genetic evaluation (University of Michigan) potential clinical significance of 1q21.1 and 22q12.22 microdeletions discussed considered at risk for NF2 and Li Fraumeni syndrome serial ophthalmologic evaluation serial otolaryngologic/audiologic evaluation annual MRI of the temporal bones beginning at age 10 years monitoring for possible cancer in adulthood Case 3. Jon B (8 years): otolaryngologic evaluation (University of Michigan) unremarkable 2012 (age 10 years): otolaryngologic followup Beaumont mild sensorineural hearing loss AD identified MRI of the brain, 8 Jun 12: small (<1 cm) acoustic schwannomata AU 2009: CMA becomes an in house test at Beaumont initial genetic evaluation: 28 Jan 11 age 4 months PICU consultation for bilateral Wilms tumor acquired hydrocephalus (intraventricular hemorrhage) small ventricular septal defect RECOMMENDATION: CMA not done Genetics Clinic follow up visit: 30 Aug 11 age 11 months interval history remarkable in part for routine chromosome analysis of Wilms tumor cells, 4 May 2011: 6,XY,t(7;8)(q36;p11)[8]/46,XY[12] routine chromosome analysis and CMA recommended WT1 analysis anticipated as a second tier investigation 30 Aug 11: request for prior authorization of routine chromosome analysis and CMA submitted 2 Sep 11: insufficient evidence in the peerreviewed, published literature to demonstrate the clinical/therapeutic utility of [CMA]... therefore not covered (based on commercial guidelines) nearly 10,000 articles regarding CMA (Mar 12) >1000 published since the beginning of : ACMG designates CMA as a second tier investigation for the genetic evaluation of unexplained DD/CI/MCA/ASD 2010: ACMG designates CMA as the first tier investigation WT1 analysis approved (Oct 11): negative 6

7 30 Aug 11: request for prior authorization of routine chromosome analysis and CMA submitted 16 Oct 12: prior authorization granted CMA (WBH, 135K oligo array) nuc ish 2q24(N MYCx3).arr2p24.3(15,568,303 16,107,873)x kb gain in copy number (duplication) at 2p24.3 including MYCN copy number gain associated with Wilms tumor also associated with neuroblastoma and other neoplasms» NBAS also duplicated neuroblastoma amplified gene mother found to share the same copy number gain reduced penetrance doing well status post right nephrectomy and partial left nephrectomy no evidence of recurrence of Wilms tumor no evidence of neuroblastoma or other neoplasm ongoing surveillance Case 5: Derrick P. 9 Dec 13: developmental delay/nonverbal LGA at birth tall stature with macrocephaly 18 Dec 13: request for prior authorization of routine chromosome analysis and molecular fragile X analysis with reflex to SNP CMA submitted 15 Jan 14: prior authorization granted 20 Jan 14: studies ordered 12 Feb 14: venipuncture Case 5: Derrick P. routine chromosome analysis (reported 23 Feb 14): 46,XY,add(15)(q26.1) molecular fragile X analysis (reported 21 Feb 14): negative (CGG repeat number = 20) SNP CMA (reported 12 Mar 14): 97.1 kb single copy loss of 15q Mb single copy gain of 15q q26.3 distal 15q overgrowth syndrome Case 6: Isabella T. 4 Feb 14 (15 months): developmental delay 4 Feb 14: SNP CMA ordered venipuncture 6 Mar 14: 3.4 Mb deletion at 18q21.2 Pitt Hopkins syndrome 7

8 Case 7: Michael M. 5 Mar 14: severe developmental delay 5 Mar 14: routine chromosome analysis and molecular fragile X analysis with reflex to SNP CMA ordered venipuncture Case 7: Michael M. routine chromosome analysis (reported 14 Mar 14): 46,XY molecular fragile X analysis (reported 12 Mar 14): negative (CGG repeat number = 30) SNP CMA (reported 2 Apr 14): 1.4 Mb single copy gain of 7q11.23 Williams Beuren region duplication syndrome 7q11.23 duplication syndrome Musings 1. Stankiewicz and Beaudet were right the clinical implementation of CMA truly has revolutionized the diagnosis of patients with syndromic or nonsyndromic cognitive impairment/developmental delay (as well as multiple congenital anomalies and/or autistic spectrum disorder). Musings 2. CMA gives a tremendous diagnostic bang for the medical buck. July 2006 $1500 ($1775 in 2014 dollars*) 853 BACs 75 genomic disorders September 2014 $1150 >2 million copy number markers ( = 2M FISH experiments) including 750,000 SNPS cf. FISH ( $250 $500/locus) *Bureau of Labor Statistics Consumer Price Index Inflation Calculator Musings 3. The sheer power of SNP CMA mandates careful pre and post test counseling inability to detect balanced rearrangements variants of unknown significance uniparental disomy consanguinity Musings 4. In my anecdotal experience and subjective opinion, the prior authorization process (and especially the fact that insurers are not required to make coverage decisions based on medical evidence) represents a significant barrier to access to CMA. 8

9 Musings 5. In my anecdotal experience and subjective opinion, the prior authorization process (and especially the fact that insurers are not required to make coverage decisions based on medical evidence) represents a significant barrier to access to newer and even more powerful technologies. whole exome sequencing whole genome sequencing 9

10 Initial Adjudication by Medicaid HMOs of CMA prior authorization requests, 12 Oct Jul requests made (11 patients) 2 approved 1 deferred pending neurological evaluation 10 denied 1 misapplication of internal coverage guidelines 2 experimental/investigational/unproven 7 will not significantly affect management 10