• Test code: 06121
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

Invitae Elevated Proline Panel

Test description

The Invitae Elevated Proline panel analyzes ALDH4A1 and PRODH, two genes that are associated with elevations of proline on newborn screening (NBS) or plasma amino-acid analysis. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions.

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Primary panel (2 genes)
  • hyperprolinemia
    • hyperprolinemia type I
    • hyperprolinemia type II

Elevated proline may be detected during newborn screening or plasma amino-acid analysis due to hyperprolinemia types I or II. Hyperprolinemia type I (HPI) is caused by pathogenic variants in the PRODH gene, which codes for the enzyme proline oxidase (POX). The enzyme breaks proline down into pyrroline-­5-­carboxylate. Hyperprolinemia type II (HPII) is caused by pathogenic variants in the ALDH4A1 gene, which codes for the enzyme 1-pyrroline-­5­-carboxylate dehydrogenase (P5CDh). P5CDh breaks pyrroline­-5­-carboxylate down into glutamate. Both enzyme deficiencies cause elevated levels of proline in the body.

In both cases, elevated proline levels are detected on newborn screening. Most individuals with pathogenic variants in PRODH and ALDH4A1 are asymptomatic, but some have seizures, cognitive issues, and psychiatric manifestations. Nephropathy has been reported in HPI. Patients with HPII are most often asymptomatic, but some affected individuals may have febrile seizures and intellectual disability. Patients with HPI and HPII will have elevated proline levels in the blood, even in asymptomatic individuals. Hyperprolinemia can also occur in liver disease and is not due to pathogenic variants in the genes.

Hyperprolinemia is inherited in an autosomal recessive manner.

The prevalence of hyperprolinemia is unknown because most individuals are asymptomatic.

This test may be considered for individuals who present with elevated proline levels in blood, cerebrospinal fluid, or urine.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ALDH4A1 NM_003748.3
PRODH* NM_016335.4

PRODH: Deletion/duplication analysis is not offered for exon 8.