Case of Autosomal Recessive METTL5 Related Intellectual Disability with Deafness
Shreya Daniel1, Megan Bone2
1School of Medicine, Johns Hopkins University School of Medicine, 2Department of Neurology at Hopkins, Kennedy Krieger Institute
Objective:

To present a case of an individual with sensorineural hearing loss and complex developmental delay who has a METTL5 homozygous mutation.

Background:
The METTL5 gene encodes an RNA-binding methyltransferase. Certain homozygous variants are associated with intellectual disability (ID), microcephaly, and other features of developmental delay. Our patient is the first documented case of sensorineural hearing loss associated with a homozygous METTL5 mutation.
Design/Methods:
This is a single clinical case report of a new clinical feature potentially associated with a known genetic mutation.
Results:

The patient is a 13-year-old girl presenting with bilateral sensorineural deafness, mild intellectual disability, attention deficit hyperactivity disorder, and history of 34-week prematurity and NICU stay for low birth weight, hypothermia, and poor feeding. Bilateral cochlear implants were placed at 15 months old. She has a broad nasal base and brachydactyly with wide thumbs and reduced finger joint mobility. The patient has disruptive behaviors and ADHD symptoms that have not improved with multiple trials of stimulants. She primarily communicates using English and ASL and has had difficulty learning Mandarin, her family’s primary language. 

Workup has included normal temporal bone CT and renal ultrasound. Initial genetic testing was negative including a targeted genetic hearing loss panel, targeted skeletal dysplasia panel (sent due to joint anomalies), and chromosomal microarray. On whole exome sequencing, the patient was homozygous for a likely pathogenic variant in METTL5. Parents and sibling were heterozygous for this variant, which causes loss of function due to splice site alteration.


Conclusions:
This case demonstrates an ultra-rare neurodevelopmental disorder with the additional key symptom of sensorineural deafness. 30-50% of patients with ID do not have syndromic features or identified genetic causes. The discovery of new ID genes like METTL5 allows us to give these patients further diagnostic clarity. This case illustrates that deafness might be part of the phenotype of this disorder.
10.1212/WNL.0000000000208379
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