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Comparing Copy Number Variations and SNPs

Comparing Copy Number Variations and SNPs

Sequencing of the human genome has opened up several best-kept secrets of the genome. Scientists have identified thousands of genome variations that exist within a population. These variations can be a single nucleotide or a larger chromosomal variation.
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...

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Detecting the Difficult: An Intronic NPC1 Variant Hiding in Plain Sight.

Caroline Gully Brown^1,2, Matthew Bower^1,3, Matthew Schomaker^1,3

¹M Health Fairview Masonic Children's Hospital, Minneapolis, Minnesota, USA.

American Journal of Medical Genetics. Part A

|March 3, 2025

Summary

Manual review of Next Generation Sequencing (NGS) data is crucial for identifying rare intronic variants. This case highlights a missed splice site variant in Niemann-Pick Type C disease, emphasizing the need for thorough data analysis.

Keywords:

NPC1 NPC1: c.1947+5G>NPC1: p.Pro237Ser NPC Niemann‐Pick disease type C intronic splice site variant

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Area of Science:

Genetics
Molecular Biology
Medical Diagnostics

Background:

Niemann-Pick Type C (NPC) disease is an autosomal recessive disorder.
Accurate genetic diagnosis requires identifying biallelic pathogenic variants.
Next Generation Sequencing (NGS) is a primary tool for genetic variant detection.

Observation:

A 14-year-old male with biochemically confirmed NPC disease initially showed only a heterozygous pathogenic variant.
Manual review of NGS data revealed a rare intronic variant (c.709C>T; p.Pro237Ser) near homopolymers.
This variant was initially overlooked due to its benign classification and potential NGS detection issues.

Findings:

The identified intronic variant (c.709C>T) was associated with a second rare intronic NPC1 variant (c.1947+5G>C).
The second variant (c.1947+5G>C) utilized a cryptic splice donor site, confirmed by Sanger sequencing.
Together, these variants explain the patient's Niemann-Pick Type C disease diagnosis.

Implications:

Manual data review is essential for detecting rare intronic variants missed by automated analysis.
Short-read NGS technologies may struggle with variants near homopolymers, necessitating careful evaluation.
Identifying all causative variants is critical for accurate diagnosis, treatment, and family genetic screening in inherited disorders.