TY  - CHAP
M1  - Book, Section
TI  - Clinical Interpretation of Genomic Data
A1  - Thakuria, Joseph V.
A1  - Murray, Michael F.
A2  - Murray, Michael F.
A2  - Babyatsky, Mark W.
A2  - Giovanni, Monica A.
A2  - Alkuraya, Fowzan S.
A2  - Stewart, Douglas R.
Y1  - 2014
N1  - 
T2  - Clinical Genomics: Practical Applications in Adult Patient Care
AB  - Genomic  technology:Advances  in  DNA  sequencing  technology  have  led  to  improved  accuracy  as  well  as  decreased  costs  and  have  resulted  in  the  recent  introduction  of  individual  whole  genome,  whole  exome,  and  large  gene  panel  sequencing  from  certified  reference  laboratories  for  clinical  molecular  diagnosis.Data  filtering:Bioinformatic  filtering  of  the  over  3  billion  nucleotide  base  pairs  found  in  any  genome  is  required  to  identify  causal  mutations.  Currently,  most  analysis  focuses  on  the  estimated  4000  genes  (out  of  a  total  of  ~20,000  genes)  in  the  human  genome  implicated  in  human  disease.Informed  consent:Prior  to  testing  patients  should  be  informed  of  (a)  potential  disclosure  of  nonpaternity,  consanguinity,  and/or  unrelatedness  to  one  or  more  family  members,  (b)  the  possibility  of  finding  either  a  diagnosis  or  predisposition  to  a  disease  unrelated  to  the  reason  that  sequencing  was  ordered,  (c)  limitations  of  current  sequencing  approaches  (even  when  genetic  etiology  is  strongly  suspected),  and  (d)  potential  risk  of  genetic  discrimination  affecting  either  insurability  and  employment.  They  should  also  be  informed  of  the  US  Federal  law  (GINA)  which  seeks  to  protect  against  the  existing  genetic  discrimination.Incidental  findings:Diagnostic  use  of  this  technology  is  made  more  complex  by  the  uncovering  of  numerous  incidental  findings  (some  with  unknown  significance  and  others  with  an  established  pathogenic  effect)  present  in  any  individual  genome.  Recent  ACMG  recommendations  on  release  of  incidental  findings  advises  the  return  of  “known  pathogenic”  and  “expected  pathogenic”  variants  identified  across  56  well  curated  genes.Genetic  counseling:Appropriate  genetic  counseling  to  address  incidental  findings  and  informed  consent  issues  is  necessary  both  prior  to  as  well  as  following  medical  genomic  testing  in  a  patient.Periodic  reanalysis:The  rapidly  evolving  knowledge  base  allows  providers  to  discuss  with  patients  the  expectation  that  future  reanalysis  of  the  same  genomic  dataset  will  yield  additional  valuable  insights  into  the  health  implications  of  the  data  for  the  patient.  Many  predict  that  annual  reanalysis  will  become  the  norm.Results  disclosure:Allowing  patients  to  “opt  out”  for  disclosure  of  abnormal  results  (even  when  findings  are  incidental  or  secondary)  is  generally  not  the  norm  in  medicine.  While  controversial,  there  may  be  special  instances  in  medical  genomics  where  providing  an  “opt  out”  option  for  abnormal  results  is  appropriate  -  such  as  when  incidental  findings  for  an  adult-onset  disease  in  a  pediatric  patient  is  discovered.  Even  in  these  cases,  however,  disclosure  to  the  parents/guardians  is  generally  favored  over  suppression  of  these  results.Sanger  sequencing:The  use  of  traditional  DNA  sequencing  approaches  to  genetic  diagnosis  (ie,  Sanger  sequencing)  continues  to  have  a  clinical  role  in  the  diagnosis  of  many  well-studied  conditions.  Currently,  pathogenic  mutations  generated  from  next-generation  sequencing  (NGS)  are  usually  confirmed  with  an  alternative  method  of  clinical  sequencing  before  being  medically  acted  upon  and  Sanger  sequencing  is  often  considered  the  “gold  standard”  for  confirmation.Limitations  of  NGS:Current  technology  does  not  perfectly  represent  the  complete  genome  or  exome  due  to  technical  limitations.  At  this  time,  clinical  exome  sequencing  on  average  covers  92-99%  or  more  of  targeted  coding  areas  of  genes  and  provides  a  diagnostic  yield  in  around  one-quarter  of  cases  when  applied  to  highly  selected  scenarios  of  “diagnostic  unknowns.”  Some  causative  mutations,  such  as  trinucleotide  repeat  expansions  in  disorders  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/16
UR  - accessbiomedicalscience.mhmedical.com/content.aspx?aid=1102707493
ER  -