Invitae Hyperprolinemia Panel


Test description

The Invitae Hyperprolinemia panel analyzes two genes, ALDH4A1 and PRODH, which are known to cause hyperprolinemia—excess proline accumulation in the body. There are two types of hyperprolinemia, I and II. Genetic testing of the genes in this panel may confirm a diagnosis and help guide treatment and management decisions.

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Primary panel (2 genes)


Hyperprolinemia type I, hyperprolinemia type II

Hyperprolinemia type I (HPI) is caused by pathogenic variants in the PRODH gene, which codes for the enzyme proline oxidase (POX). POX 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.

With both types of hyperprolinemia, elevated proline levels are detected upon 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; this type 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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

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