Newborn screening for familial hypercholesterolaemia using first-tier biochemical testing followed by reflex second-tier genetic testing could substantially increase diagnosis and provide opportunities for cascade screening, a study has shown.
A team of US and UK researchers assessed the feasibility of multi-tier newborn screening for familial hypercholesterolaemia, finding that the genetic disorder was identified among newborns at rates consistent with those of older children, although further refinement and validation were needed.
They tested 10,004 residual newborn dried blood spot specimens collected from a cohort of 59,927 newborns for total cholesterol, low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB) between the first 24 and 72 hours of life.
From the specimens tested, principal component analysis demonstrated that the combination of LDL-C and ApoB accounted for the greatest variance.
The researchers then selected the specimens with the highest levels of LDL-C and ApoB for genetic testing, with 768 specimens included in total.
Findings published in a brief report for JAMA Cardiology [link here] showed a pathogenic variant for familial hypercholesterolaemia identified in 16 samples, yielding a population-based prevalence of 1 in 625 (1.6 per 1000) newborns.
The researchers said at the very least their approach should detect all newborns with homozygous variant for familial hypercholesterolaemia as those newborns would have the most extreme elevations in LDL-C and ApoB levels.
A biochemical first approach also substantially lowered cost, they said.
“Even if our approach only identifies 50% of individuals with familial hypercholesterolaemia, this will raise current familial hypercholesterolaemia diagnosis rates (currently 5%-10%) tremendously,” they said.
“If newborn screening for familial hypercholesterolaemia is implemented clinically, a multi-pronged approach would likely be adopted to ensure that newborns with high LDL-C and ApoB levels but negative genetic testing results are still investigated and monitored as high risk.
“If any variants of uncertain significance are later reclassified as pathogenic or if a larger proportion of specimens underwent genetic testing, this would increase our genotypically confirmed familial hypercholesterolaemia prevalence.”
Writing in an accompanying commentary [link here], US doctors from the Children’s Hospital of Philadelphia said there was a “strong case” for inclusion of at least homozygous familial hypercholesterolaemia in newborn screening protocols, enabling earlier therapeutic intervention to improve health outcomes.
They highlighted that cardiovascular consequences of familial hypercholesterolaemia were “eminently preventable”, citing a long-term study that showed statin therapy initiated in childhood slowed progression of atherosclerosis and participants also had less clinical cardiovascular disease as adults.
But the commentary agreed with the study authors on the need for refinement.
“The high discrepancies between values from different batches of LDL-C/ApoB testing raise concerns for both producing false negatives and false positives. In addition, no molecular testing was performed on individuals with normal biomarkers, drawing into question the sensitivity of the test to identify individuals with pathogenic familial hypercholesterolaemia variants with normal biomarkers at birth,” they said.
“The sensitivity and specificity for detection of homozygous familial hypercholesterolaemia, where the most urgent intervention in childhood is needed, is unknown.”
They said other important questions that would need to be worked out before implementation included how follow up and medical management would work for infants who screened positive, and how to ensure at-risk relatives get screened.