Effectiveness of newborn screening for X-linked disorders in females: A scoping review
Hanabi Geiger1, Yutaka Furuta1, John A Phillips1
1Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Insights
Newborn screening (NBS) rarely detects X-linked (XL) conditions in females, despite their clinical relevance. Current screening lacks sex-specific data, potentially missing affected female newborns.
Area of Science:
- Genetics
- Neonatal Medicine
- Public Health
Background:
- Newborn screening (NBS) is crucial for early detection of genetic disorders.
- X-linked (XL) conditions are increasingly recognized as affecting females, not just males.
- Existing NBS protocols may not adequately identify XL conditions in females.
Purpose of the Study:
- To evaluate the efficacy of current NBS protocols in detecting X-linked genetic disorders in females.
- To identify gaps in NBS data reporting regarding sex-specific outcomes for XL conditions.
Main Methods:
- Conducted a scoping review of 12 XL genetic disorders included in NBS panels.
- Systematically searched literature for studies reporting NBS outcomes for these conditions.
- Analyzed data on the detection of female cases in published NBS studies.
Main Results:
- All 12 reviewed XL disorders can affect females, often with milder symptoms due to X-inactivation.
- Only 50% of these conditions had relevant NBS data, and female cases were infrequently reported.
- Detection of female cases was low (42% of studies), potentially due to biomarker levels within normal ranges caused by skewed X-inactivation.
Conclusions:
- Current NBS practices inadequately detect XL conditions in females and often lack sex-specific data.
- This highlights a significant gap in reporting and equitable screening for all newborns.
- Improvements may involve sex-specific thresholds, alternative biomarkers, or genetic testing to ensure comprehensive NBS.
Purpose:
Newborn screening (NBS) identifies thousands of infants annually with conditions amenable to early intervention. Although several X-linked (XL) conditions in NBS panels are viewed as primarily male disorders, emerging evidence shows females also present clinically. This scoping review evaluates NBS efficacy for detecting XL conditions in females.
Methods:
Twelve XL genetic disorders were identified through cross-referencing the Recommended Uniform Screening Panel, American College of Medical Genetics ACT sheets, and available literature. A systematic search and scoping review identified studies reporting NBS outcomes.
Results:
All twelve XL disorders reviewed affect females, often with milder phenotypes, likely due to X-inactivation. However, only 6/12 (50 %) of these conditions had relevant NBS data, and female cases were rare. Only 92/221 (42 %) of the studies included detected female cases. Skewed X-inactivation may modulate expression, leading to biomarker levels within reference ranges and reducing detection.
Conclusions:
Although XL conditions affect both sexes, current NBS protocols rarely detect females or don't report sex-specific data at all. This absence highlights broader gaps in how screening outcomes are reported. Addressing these limitations may require sex-specific biomarker thresholds, alternative biomarkers, or genetic testing. Such efforts are necessary to ensure that NBS programs equitably serve all affected newborns.
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