Challenges in Microarray Analysis and Interpretation of Incidental Findings on the X Chromosome
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction
Chromosomal microarray (CMA) is recommended as first-tier testing for individuals with developmental delay, intellectual disability, autism, and/or multiple congenital anomalies. CMA’s high resolution and advances in software development have increased the diagnostic yield, improved clinical interpretation, and reduced turnaround times. However, genome-wide testing may uncover copy number variants (CNVs) unrelated to the referral reason. The ACMG recommends reporting of all pathogenic and likely pathogenic CNVs to aid clinical intervention, though their significance to the individual tested remains unclear in some cases. This may be due to incomplete penetrance, variable expressivity, or X-chromosome inactivation. We present a case of a female with an incidental finding of an X;Y translocation resulting in an SRY-positive female. The presence of Y material was not called by the analysis software, emphasizing the importance of manual data review. Previous case reports of X;Y translocations have shown phenotypic variability, often influenced by X-chromosome inactivation patterns, complicating the prediction of its phenotypic impact in females.
Case Presentation
A four-month-old female presented with webbed neck, short stature, microcephaly, failure to thrive, dysmorphic facial features, cardiac murmur, ventricular septal defect, abnormal transaminases, and haematochezia. No clinical suspicion of differences of sex development (DSD) was noted. CMA testing was requested.
Diagnostic Workup
A 1.9 Mb pathogenic deletion was identified at 7p22.2p22.1, which is the likely cause of this individual’s phenotype. On the X chromosome, a 5.3 Mb terminal pathogenic deletion at Xq28 and a 2.6 Mb terminal duplication of Xp22.33 overlapping PAR1 was called by the analysis pipeline.
Manual review of array data revealed the presence of Yp material which included the SRY gene. The chromosomal sex was predicted to be female by the analysis software, and the gain of Yp was not flagged. This is likely due to the PAR regions being displayed on the X chromosome, regardless of whether it originates from the X or Y chromosome. This suggests the PAR1 gain was from the Y chromosome indicative of a translocation. Karyotype analysis confirmed a derivative chromosome X from an X;Y translocation [46,X,der(X)t(X;Y)(q28;p11.2)].
Treatment and Management
NA
Outcome and Follow-Up
Detailed anatomical imaging of the individual is necessary to exclude the presence of DSD. Maternal karyotype analysis is recommended to establish whether the translocation is inherited or de novo. If maternal inheritance is confirmed, there may be an increased risk of miscarriage due to the lethality of Xq28 deletion in male offspring. Given the mother’s reproductive age and history of prior miscarriage, the findings carry important implications for reproductive management.
Discussion
Xq/Yp translocations are rare, with limited reported cases in the literature. Most X/Y (SRY+) translocations involve the Xp region and carriers are phenotypically male but may develop DSD, abnormal hormones levels, gonadal tumors, or infertility. The few reported cases of Xq/Yp translocation display wide phenotypic variability. One case report described a female with Xq/Yp translocation with ovotesticular DSD. Additionally, a family case study noted four females across three generations with a t(X;Y)(q28;p11.2)(SRY+) translocation with normal sexual development, attributed to preferential inactivation of the derivative X chromosome. In our case study, the size of the Xq28 deletion and absence of DSD phenotype suggest preferential inactivation of the derivative X chromosome, although further familial testing is required.
Conclusion
Technological advancements have increased reliance on automated pipelines for CNV calling and interpretation; however, their limitations may lead to incorrect conclusions. In this case, the initial findings of a terminal gain of Xp and terminal loss of Xq could have been suggestive of a recombinant chromosome instead of an X/Y translocation. Additionally, the genetic counseling of incidental findings can be challenging due to phenotypic variability of certain CNVs.
Chromosomal microarray (CMA) is recommended as first-tier testing for individuals with developmental delay, intellectual disability, autism, and/or multiple congenital anomalies. CMA’s high resolution and advances in software development have increased the diagnostic yield, improved clinical interpretation, and reduced turnaround times. However, genome-wide testing may uncover copy number variants (CNVs) unrelated to the referral reason. The ACMG recommends reporting of all pathogenic and likely pathogenic CNVs to aid clinical intervention, though their significance to the individual tested remains unclear in some cases. This may be due to incomplete penetrance, variable expressivity, or X-chromosome inactivation. We present a case of a female with an incidental finding of an X;Y translocation resulting in an SRY-positive female. The presence of Y material was not called by the analysis software, emphasizing the importance of manual data review. Previous case reports of X;Y translocations have shown phenotypic variability, often influenced by X-chromosome inactivation patterns, complicating the prediction of its phenotypic impact in females.
Case Presentation
A four-month-old female presented with webbed neck, short stature, microcephaly, failure to thrive, dysmorphic facial features, cardiac murmur, ventricular septal defect, abnormal transaminases, and haematochezia. No clinical suspicion of differences of sex development (DSD) was noted. CMA testing was requested.
Diagnostic Workup
A 1.9 Mb pathogenic deletion was identified at 7p22.2p22.1, which is the likely cause of this individual’s phenotype. On the X chromosome, a 5.3 Mb terminal pathogenic deletion at Xq28 and a 2.6 Mb terminal duplication of Xp22.33 overlapping PAR1 was called by the analysis pipeline.
Manual review of array data revealed the presence of Yp material which included the SRY gene. The chromosomal sex was predicted to be female by the analysis software, and the gain of Yp was not flagged. This is likely due to the PAR regions being displayed on the X chromosome, regardless of whether it originates from the X or Y chromosome. This suggests the PAR1 gain was from the Y chromosome indicative of a translocation. Karyotype analysis confirmed a derivative chromosome X from an X;Y translocation [46,X,der(X)t(X;Y)(q28;p11.2)].
Treatment and Management
NA
Outcome and Follow-Up
Detailed anatomical imaging of the individual is necessary to exclude the presence of DSD. Maternal karyotype analysis is recommended to establish whether the translocation is inherited or de novo. If maternal inheritance is confirmed, there may be an increased risk of miscarriage due to the lethality of Xq28 deletion in male offspring. Given the mother’s reproductive age and history of prior miscarriage, the findings carry important implications for reproductive management.
Discussion
Xq/Yp translocations are rare, with limited reported cases in the literature. Most X/Y (SRY+) translocations involve the Xp region and carriers are phenotypically male but may develop DSD, abnormal hormones levels, gonadal tumors, or infertility. The few reported cases of Xq/Yp translocation display wide phenotypic variability. One case report described a female with Xq/Yp translocation with ovotesticular DSD. Additionally, a family case study noted four females across three generations with a t(X;Y)(q28;p11.2)(SRY+) translocation with normal sexual development, attributed to preferential inactivation of the derivative X chromosome. In our case study, the size of the Xq28 deletion and absence of DSD phenotype suggest preferential inactivation of the derivative X chromosome, although further familial testing is required.
Conclusion
Technological advancements have increased reliance on automated pipelines for CNV calling and interpretation; however, their limitations may lead to incorrect conclusions. In this case, the initial findings of a terminal gain of Xp and terminal loss of Xq could have been suggestive of a recombinant chromosome instead of an X/Y translocation. Additionally, the genetic counseling of incidental findings can be challenging due to phenotypic variability of certain CNVs.