Exome sequencing finds a novel PCSK1 mutation in a child with generalized malabsorptive diarrhea and diabetes insipidus.

Congenital diarrheal disorders are uncommon yet frequently devastating chronic conditions that are secondary to a diverse group of autosomal recessive mutations. They can be classified into those that selectively impair the transport or hydrolysis of single nutrients or electrolytes and those that attenuate the assimilation of all forms of nutrients (1). They may also be grouped as either malabsorptive or secretory in nature, and by an array of histologic features, including changes within the enterocytes or their migration along the crypt–villus axis. Regardless, children presenting shortly after birth with severe diarrhea—given their rarity and heterogeneity—are frequently misdiagnosed. Failure to diagnose such patients quickly and accurately can undermine their tenuous hold on life. When correctly diagnosed, subjects with impairment of selective nutrient assimilation generally do well on a lifelong nutrient-specific restricted diet; however, those presenting with malabsorption of multiple forms of nutrients (proteins, carbohydrates, and fats) generally have an adverse clinical course that includes lifelong or prolonged total intravenous (parenteral) nutrition, and/or intestinal and occasionally concomitant liver transplantation (1). Although these disorders are frequently fatal without proper dietary and nutritional modifications, present state-of-the-art therapeutic modalities are primitive and are associated with extremely significant morbidity and mortality, as well as daunting medical care costs (2). As a group, generalized malabsorptive diarrheal disorders are frequently idiopathic, and their physiologic basis is poorly understood (3). These limitations serve as the impetus to a general search for the molecular basis of these disorders, thus propelling the use of recently feasible pluripotent and somatic stem cell technologies to discover alternative therapeutic approaches (4). In some cases, the histology and nutrient absorption characteristics may point to the possibility of dysfunction in known genes (Neurogenin-3 [NEUROG3], SGLT1, EPCAM, MYO5B, SPINT2, TTC37, SKIV2L, ADAM17), which can then be directly sequenced to identify likely causative mutations (5–11). Often, however, clinical evidence may be insufficient to implicate known genes or sequencing of candidate genes fails to reveal damaging mutations resulting from genetic heterogeneity. These aspects, as is typical of all rare disorders, greatly impede efficient and timely diagnosis. Recent advances in sequencing technology now make it possible to sequence the coding portion and essential splice sites of approximately 95% of all protein-coding bases of all known genes (the “exome”) at a cost comparable to clinical sequencing tests of a single gene (12,13). Thus, an unbiased scan of the exome can discover known and novel mutations in known genes and also mutations in hitherto unsuspected genes in a manner that efficiently directs clinical care. Here we show an example of the use of whole-exome sequencing to identify the causative mutation in a child with congential diarrhea. Prohormone convertase 1/3 (PC1/3) is a calcium-dependent serine endoprotease that converts proinsulin and other prohormones into active forms (14). PC1/3 is highly expressed in the small intestine. PC1/3 deficiency, resulting from the mutations in the pro-protein convertase subtilisin/kexin type 1 (PCSK1) gene, can prevent enteroendocrine cells from producing functional hormones and cause generalized malabsorption and a variety of systemic endocrinopathies that develop in an age-dependent fashion (15). The mechanism by which PC1/3 deficiency causes malabsorption is not well understood, but it may be that a novel peptide, or multiple redundant peptides, processed by PC1/3 enhance nutrient assimilation.