Small and large mutations: how do we sail among different mutation sizes?

How large can a mutation be?

Genetic variations in the human genome can differ very much in size. Starting from the smallest mutations possible, the SNV (single nucleotide variation), up to the deletion of an entire chromosome, you can find mutations of every size in the middle! The vast majority of pathogenic mutations are SNVs or small indels, which may be detected by standard sequencing, e.g. whole exome sequencing, whole genome sequencing, multigene panel testing, or single gene analysis by capillary electrophoresis (Sanger sequencing).

However, a smaller portion of pathogenic mutations is consistent with larger genetic abnormalities, which most often are represented by gain or loss of entire parts of the genomic sequence, thus also known as Copy Number Variations (CNVs). The size of CNVs is usually comprised between 1,000 bp (1Kbp) and 1,000,000 bp (1Mbp). CNV analysis may be performed through one or more of the following methods: array-CGH, SNP-array, MLPA, qPCR, or algorithmic CNV testing based on Next Generation Sequencing (NGS) data (e.g. data from whole exome sequencing, standard whole genome sequencing 30x, or low-pass whole genome sequencing at 5x – LP-GS).

When testing a patient, is it better to start with small mutations or CNV analysis?

The standard genetic testing approach to the diagnosis of rare diseases starts with pure sequence analysis, i.e. the scanning of small mutations. However, the mutational spectrum of some genes may be very specific, is mainly characterized by the occurrence of large mutations. Whenever there’s a strong clinical suspicion for a particular disorder or syndrome caused by mutation in one of those genes, i.e. when the treating physician recognizes typical clinical signs in the patient’s features resembling that particular disorder, genetic testing may start by doing CNV analysis for that particular gene.

Which genes are mainly characterized by large mutations?

There are several examples of genes with a specific mutational spectrum, where large mutations (CNVs) are more frequent than SNVs. Putting together a thorough list it’s difficult, also considering that several new gene-disease associations are discovered every year. However, we may certainly recall some genes among the most frequently tested one. In the table below, we have prepared a selection for you. If you are in doubt about any gene you have in mind, please do not hesitate to contact us!


Gene Disease Proportions of CNVs as cause of the disorder (approximately)
SMN1 Spinal muscular atrophy 95%-98% of cases with bi-allelic large deletions which always include exon 7.

2%-5% of cases with a large deletion including exon 7 in compound heterozygous with an intragenic pathogenic variant.

RAI1 Smith-Magenis syndrome 90% of cases with a heterozygous deletion of chromosomal region 17p11.2. Among them:

70% of cases with a recurrent deletion of 3.5 MB; 20% of cases with deletions of different sizes.

PMP22 Hereditary neuropathy with liability to pressure palsies  Charcot-Marie-Tooth 1A 80% of cases with a heterozygous deletion of 1.5Mb including the whole gene.

70% of cases with a heterozygous duplication of 1.5Mb including the whole gene.


SHOX SHOX deficiency disorders 70-75% of cases with CNVs (deletions including the whole gene as well as adjacent genes, partial and complete duplications of the gene).
DMD Dystrophinopathies

(Duchenne Muscular Dystrophy, DMD

Becker Muscular Dystrophy, BMD)

65%-80% of cases with CNVs (60%-70% of DMD and BMD cases with deletions of one or more exons; 5%-10% of BMD cases with partial duplications).
PLP1 PLP1 disorders 60%-70% of cases with CNVs (the vast majority are duplications, but higher multiplications are reported; deletion of the whole gene and complex CNVs also occur).
PRKN Juvenile Parkinson’s disease >50% of cases with exon or multi-exon deletions, duplications and triplications.

How do we deal with CNVs at Breda Genetics?

For all those particular genes where the mutational spectrum is known to be mainly characterized by large deletions or duplications, we usually recommend starting with a targeted molecular approach for that single gene (MLPA or qPCR). Doing a small multigene panel testing by mixing sequencing and targeted CNV testing for multiple genes, in order to cover the differential diagnosis, may also be a good strategy (e.g. sequencing plus MLPA or high-density array-CGH). Conversely, if the clinical suspicion is not well defined, we usually proceed to exome/genome-wide algorithmic CNV analysis based on whole exome sequencing or whole genome sequencing, most often after having done SNV scanning.

If you would like to make an enquiry about any particular clinical case of yours to learn whether it may be better to perform whole exome sequencing or targeted CNV analysis first, please do not hesitate to contact us by sending an e-mail to, or by utilizing the contact form here below.

[siteorigin_widget class=”FrmShowForm”][/siteorigin_widget]


Leave a Reply

Your email address will not be published. Required fields are marked *

Feel free to call us to book your appointment



Enter Email
Confirm Email

Subscribe to our newsletter to receive news on the world of genetics.

We regularly send specific information for Patients and Professionals with updates and news.
No Spam, that's information.

Newsletter Signup

Newsletter Signup