Frigeni M1, Balakrishnan B1, Yin X1, Pasquali M1,2,3, Longo N1,2,3.

1Dept Pediatrics, 2Pathology, and 3ARUP Laboratories, University of Utah, Salt Lake City, UT, USA.

Email: Phone: 801-585-9558

Primary carnitine deficiency is a recessive disorder of the carnitine cycle caused by mutations in the SLC22A5 gene. Patients can present with an acute metabolic decompensation early in life,

or later in life with skeletal and cardiac myopathy or sudden death from arrhythmia. The diagnosis, suspected because of clinical presentation or low levels of free carnitine in the newborn screening, can be confirmed by functional studies in fibroblasts or by SLC22A5 gene sequencing.

Here we compare functional studies to gene sequencing for the diagnostic confirmation of primary carnitine deficiency.

Carnitine transport was measured in skin fibroblasts of 382 patients suspected of having primary carnitine deficiency. SLC22A5 gene sequencing was performed in 95 patients with reduced carnitine transport. Missense variants identified were expressed in CHO cells and tested for carnitine transport.

Carnitine transport was reduced to ≤20% of normal in fibroblasts of 140/382 subjects.

SLC22A5 gene sequencing in 95/140 subjects identified variants in 84% of the alleles. Expression of 88 missense changes (33 novel) in CHO cells demonstrated reduced carnitine transport in 73/88. Prediction algorithms (SIFT, Polyphen-2) correctly predicted the functional effects of missense variants in 77% of cases.

These results indicate that functional studies remain the best strategy to confirm or exclude a diagnosis of primary carnitine deficiency, since DNA sequencing of the SLC22A5 gene fails to identify causative variants in about 16% of the alleles and existing software can correctly predict the pathogenicity of missense variants in only 77% of cases.

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