title: Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations.
abstract: BACKGROUND
  Noninvasive prenatal testing can be used to accurately detect chromosomal aneuploidies in circulating fetal DNA; however, the necessity of parental haplotype construction is a primary drawback to noninvasive prenatal diagnosis (NIPD) of monogenic disease. Family-specific haplotype assembly is essential for accurate diagnosis of minuscule amounts of circulating cell-free fetal DNA; however, current haplotyping techniques are too time-consuming and laborious to be carried out within the limited time constraints of prenatal testing, hampering practical application of NIPD in the clinic. Here, we have addressed this pitfall and devised a universal strategy for rapid NIPD of a prevalent mutation in the Ashkenazi Jewish (AJ) population.
  
  
  METHODS
  Pregnant AJ couples, carrying mutation(s) in GBA, which encodes acid β-glucosidase, were recruited at the SZMC Gaucher Clinic. Targeted next-generation sequencing of GBA-flanking SNPs was performed on peripheral blood samples from each couple, relevant mutation carrier family members, and unrelated individuals who are homozygotes for an AJ founder mutation. Allele-specific haplotypes were constructed based on linkage, and a consensus Gaucher disease-associated founder mutation-flanking haplotype was fine mapped. Together, these haplotypes were used for NIPD. All test results were validated by conventional prenatal or postnatal diagnostic methods.
  
  
  RESULTS
  Ten parental alleles in eight unrelated fetuses were diagnosed successfully based on the noninvasive method developed in this study. The consensus mutation-flanking haplotype aided diagnosis for 6 of 9 founder mutation alleles.
  
  
  CONCLUSIONS
  The founder NIPD method developed and described here is rapid, economical, and readily adaptable for prenatal testing of prevalent autosomal recessive disease-causing mutations in an assortment of worldwide populations.
  
  
  BACKGROUND
  SZMC, Protalix Biotherapeutics Inc., and Centogene AG.
authors.forename: David A
authors.initials: DA
authors.lastname: Zeevi
authors.forename: Gheona
authors.initials: G
authors.lastname: Altarescu
authors.forename: Ariella
authors.initials: A
authors.lastname: Weinberg-Shukron
authors.forename: Fouad
authors.initials: F
authors.lastname: Zahdeh
authors.forename: Tama
authors.initials: T
authors.lastname: Dinur
authors.forename: Gaya
authors.initials: G
authors.lastname: Chicco
authors.forename: Yair
authors.initials: Y
authors.lastname: Herskovitz
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.forename: Deborah
authors.initials: D
authors.lastname: Elstein
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.forename: Ari
authors.initials: A
authors.lastname: Zimran
mesh_terms: D000483:Alleles; D016384:Consensus Sequence; D004247:DNA / Q000097:blood* / Q000235:genetics; D004252:DNA Mutational Analysis; D042241:Early Diagnosis; D005260:Female; D005315:Fetal Diseases / Q000175:diagnosis* / Q000235:genetics; D005331:Fetomaternal Transfusion; D018703:Founder Effect; D005776:Gaucher Disease / Q000175:diagnosis* / Q000196:embryology / Q000235:genetics; D005808:Genes, Recessive; D005962:Glucosylceramidase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007585:Jews / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA; D013997:Time Factors
chemical_list: D004247:DNA; D005962:Glucosylceramidase