Abstract
BackgroundMale sex chromosome aneuploidies are underdiagnosed despite concomitant physical and behavioral manifestations.ObjectiveTo develop a non-invasive, rapid and high-throughput molecular diagnostic assay for detection of male sex chromosome aneuploidies, including 47,XXY (Klinefelter), 47,XYY, 48,XXYY and 48,XXXY syndromes.MethodsThe assay utilizes three XYM and four XA markers to interrogate Y:X and X:autosome ratios, respectively. The seven markers were PCR amplified using genomic DNA isolated from a cohort of 323 males with aneuploid (n = 117) and 46,XY (n = 206) karyotypes. The resulting PCR products were subjected to Pyrosequencing, a quantitative DNA sequencing method.ResultsReceiver operator characteristic (ROC) curves were used to establish thresholds for the discrimination of aneuploid from normal samples. The XYM markers permitted the identification of 47,XXY, 48,XXXY and 47,XYY syndromes with 100% sensitivity and specificity in both purified DNA and buccal swab samples. The 48,XXYY karyotype was delineated by XA marker data from 46,XY; an X allele threshold of 43% also permitted detection of 48,XXYY with 100% sensitivity and specificity. Analysis of X chromosome-specific biallelic SNPs demonstrated that 43 of 45 individuals (96%) with 48,XXYY karyotype had two distinct X chromosomes, while 2 (4%) had a duplicate X, providing evidence that 48,XXYY may result from nondisjunction during early mitotic divisions of a 46,XY embryo.ConclusionsQuantitative Pyrosequencing, with high-throughput potential, can detect male sex chromosome aneuploidies with 100% sensitivity.
Highlights
Klinefelter syndrome (KS, known as 47,XXY) and 47,XYY syndrome are the two most common sex chromosome aneuploidies in humans with prevalence of approximately 1 in 600–1000 males [1,2,3,4]
Compared to 46,XY males, individuals with KS or 47,XYY syndrome exhibit a greater incidence of behavioral problems, psychiatric disorders and neuropsychological characteristics including developmental delays and difficulties in cognitive, verbal and social skills [5]
Newborn screening studies estimate that only 25% of all individuals with KS, and 10% of all individuals with 47, XYY are diagnosed during their lifetime [6,7]
Summary
Klinefelter syndrome (KS, known as 47,XXY) and 47,XYY syndrome are the two most common sex chromosome aneuploidies in humans with prevalence of approximately 1 in 600–1000 males [1,2,3,4]. Compared to 46,XY males, individuals with KS or 47,XYY syndrome exhibit a greater incidence of behavioral problems, psychiatric disorders and neuropsychological characteristics including developmental delays and difficulties in cognitive, verbal and social skills [5]. Individuals with both syndromes often fail to be ascertained. Male sex chromosome aneuploidies are underdiagnosed despite concomitant physical and behavioral manifestations
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