Development of a diagnostic DNA chip to screen for 30 autosomal recessive disorders in the Hutterite population

Abstract

BackgroundThe Hutterites are a religious isolate living in colonies across the North American prairies. This population originated from approximately 90 founders, resulting in a number of genetic diseases that are overrepresented, underrepresented, or unique. The founder effect in this population increases the likelihood that Hutterite couples carry the same recessive mutations. We have designed a diagnostic chip on a fee‐for‐service basis with Asper Biotech to provide Hutterites with the option of comprehensive carrier screening.MethodsA total of 32 disease‐causing mutations in 30 genes were selected and primers were designed for array primer extension‐based testing. Selected mutations were limited to those leading to autosomal recessive disorders, maintaining its primary use as a test for determining carrier status.ResultsThe DNA chip was developed and validated using 59 DNA controls for all but one of the mutations, for which a synthetic control was used. All mutations were readily detected except for a duplication causing restrictive dermopathy where heterozygotes and homozygotes could only be distinguished by sequencing. Blinded testing of 12 additional samples from healthy Hutterites was performed by Asper Biotech using chip testing. All known mutations from previous molecular testing were detected on the chip. As well, additional mutations identified by the chip in these 12 samples were subsequently verified by a second method.ConclusionsOur analysis indicates that the chip is a sensitive and specific means of carrier testing in the Hutterite population and can serve as a model for other founder populations.

Diphthamide affects selenoprotein expression: Diphthamide deficiency reduces selenocysteine incorporation, decreases selenite sensitivity and pre-disposes to oxidative stress

“…Some ovarian tumors display loss of heterozygosity of the diphthamide synthesis gene DPH1 DPH1 =tumor suppressor gene OVCA1; [50] and mutations in diphthamide synthesis genes that affect their expression are present in other tumors [51] . Additionally, several independent studies link mutations in DPH1 with inherited developmental/neuronal disorders [52] , [53] , [54] , [55] , [56] . The observation of developmental deficiencies in patients carrying mutations in diphthamide synthesis genes may reflect the relevant roles of NFkB in development and correlate with developmental defects of DPHko mice [14] , [57] , [58] .…”

Prevalence rates study of selected isolatednon‐Mendeliancongenital anomalies in the Hutterite population of Alberta, 1980–2016

“…There are numerous publications on autosomal recessive traits in the Hutterite Brethren (HB), many of them very rare (Boycott et al, 2008; Triggs‐Raine et al, 2016). The objectives of this study were to update information on the prevalence of the more common non‐Mendelian congenital anomalies and to compare these rates with the general population of Alberta.…”