Objective:

Genomic tools, such as chromosomal microarray analysis and exome sequencing, allow for detection of copy number variants (CNVs) or single nucleotide variants (SNVs) in patients with suspected genetic conditions. However, these tools do not detect an important component of gene transcription which is the 5’ untranslated region (5’UTR). We hypothesize that when there is alteration of mRNA gene expression in the 5’UTR of a dosage-sensitive gene, this defect could lead to a clinical phenotype. 

Background:

Therefore, to confirm the importance of the 5’ UTR, we investigated CNV losses in MBD5 which is associated with 2q23.1 deletion syndrome. 2q23.1 deletion syndrome is one of the many disorders that are grouped under MBD5-associated neurodevelopmental disorder (MAND). These disorders affect the function of MBD5 and share developmental disabilities, neurological disturbances, language impairments, and hyperactive behavior. 

Design/Methods:

Patients were recruited with deletions in the 5’ UTR region of MBD5 to evaluate whether these deletions may be responsible for haploinsufficiency of MBD5 which is present in all 2q23.1 deletion patients. The patients were grouped based on their 5’UTR MBD5 deletions into six categories of deletions.

Results:

Genotype-phenotype studies of these deletions revealed that Category 1 5’UTR deletion phenotypes resembled a traditional MAND phenotype.  We conducted qPCR studies to evaluate the mRNA expression of the various 5’UTR deletions. We saw decreased MBD5 mRNA expression in Category 1 and Category 3.  

Conclusions:

This study confirms the importance of careful assessment of the 5’ UTR in clinical genetics testing, particularly for dosage-sensitive genes for we could be missing genetic diagnoses.