Compound Heterozygous Complete Loss-of-Function SPINK1 Variants as a Novel Cause of Severe Infantile Isolated Exocrine Pancreatic Insufficiency.

BACKGROUND/OBJECTIVES: While complete loss-of-function (LoF) SPINK1 variants in the simple heterozygous state cause chronic pancreatitis, biallelic complete LoF variants result in a rare pediatric disorder termed severe infantile isolated exocrine pancreatic insufficiency (SIIEPI). To date, only two individuals with a null SPINK1 genotype have been reported-one homozygous for a whole-gene deletion and the other for an Alu insertion in the 3' untranslated region. Here, we report the genetic basis of a third SIIEPI case, presenting in early infancy with severe exocrine pancreatic insufficiency and diffuse pancreatic lipomatosis.

METHODS: Targeted next-generation sequencing (NGS) was used to analyze the entire coding region and exon-intron boundaries of the SPINK1 gene. Copy number variant (CNV) analysis was performed with SeqNext, based on normalized amplicon coverage.

RESULTS: The proband harbored compound heterozygous complete LoF SPINK1 variants. One was the known NM_001379610.1:c.180_181del (p.(Cys61PhefsTer2)), inherited from the father. The second, initially detected as an exon 2 deletion and confirmed by quantitative fluorescent multiplex PCR (QFM-PCR), was further characterized by long-range PCR as a complex rearrangement comprising a 1185 bp deletion removing exon 2, a 118 bp templated insertion followed by a non-templated nucleotide, and an 8 bp deletion. The mutational signature is consistent with serial replication slippage or template switching involving translesion synthesis. This maternally inherited variant has not been previously reported.

CONCLUSIONS: This study expands the mutational spectrum of SPINK1-related SIIEPI and suggests that this distinct pediatric disorder may be under recognized in clinical practice.