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Detecting the Difficult: An Intronic NPC1 Variant Hiding in Plain Sight
Author(s) -
Brown Caroline Gully,
Bower Matthew,
Schomaker Matthew,
Goldstein Jessica,
Jarnes Jeanine,
Whitley Chester B.,
Pillai Nishitha R.
Publication year - 2025
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.64012
Subject(s) - npc1 , genetics , sight , biology , computational biology , physics , astronomy , endosome , intracellular
ABSTRACT An illustration of the importance of manual data review for identifying rare intronic variants adjacent to homopolymers is presented here. A 14‐year‐old male with Niemann‐Pick Type C disease confirmed biochemically was only found to have a heterozygous pathogenic variant by molecular analysis. A manual review of the Next Generation Sequencing (NGS) data identified a c.709C>T; p.Pro237Ser variant, which was likely not reported initially because it is consistently classified as benign or likely benign. A rare association of the c.709C>T variant with a second intronic NPC1 variant (c.1947 + 5G>C) leading to the use of a cryptic splice donor site has been reported before. Further evaluation with Sanger sequencing detected the c.1947 + 5G>C variant as the second causative variant in this patient. Detection of a second allelic change in autosomal recessive inborn errors of metabolism and other genetic disorders is vital in establishing a diagnosis, initiating new therapies, and testing at risk family members. The case presented here illustrates a rare intronic splice site NPC1 variant that may not be readily detected by current short‐read NGS technologies due to the downstream homopolymers and should be evaluated regularly, especially in the presence of another heterozygous variant.