Compound heterozygous mutations in MASP1 in a deaf child with absent cochlear nerves
Citation Manager Formats
Make Comment
See Comments

Abnormal cochleovestibular nerves (i.e., as absent, aplastic, or deficient) are a rare congenital malformation that have a devastating impact on hearing and language development. To date, there have been no genes identified associated with this abnormality.
Case description.
A healthy male child was born with profound sensorineural hearing loss (SNHL) and was referred for cochlear implantation (CI). Auditory brainstem response thresholds were absent or profound across all frequencies. His facial nerve function was normal on examination, and he did not have any motor delays. Vestibular testing was not performed. His evaluation included high-resolution CT and MRI of the temporal bones. CT revealed bony cochlear modioli, normal cochlear partitioning, narrow or absent cochlear apertures, enlarged vestibules, dysplastic semicircular canals, and bifid internal auditory canals (IACs). MRI revealed only 1 nerve in the lateral IAC. On the left, the IAC was too narrow in caliber to determine the contents, but findings suggested a single nerve in the lateral IAC (figure). Findings were consistent with abnormal cochleovestibular nerves bilaterally with likely absent cochlear nerves.
(A) Coronal high-resolution CT of a bifid and narrow internal auditory canal (IAC). (B) Axial high-resolution CT showing a pinpoint cochlear aperture (arrow) and an enlarged vestibule (arrowhead). Cochlear partitioning was normal, but the modiolus was bony and semicircular canals were dysplastic (not shown). (C) Axial high-resolution heavily T2-weighted (constructive interference in steady state [CISS]/fast imaging employing steady-state acquisition [FIESTA]) MRI of IACs bilaterally showing narrow IACs, one nerve in right IAC (short arrow) and nothing seen in left IAC (long arrow). Oblique cross-sectional imaging confirmed findings (not shown). (D) Family pedigree showing the mutations in MASP1. (E) Sanger sequencing traces showing the mutations inherited in the pedigree.
The child underwent a single cochlear implant and demonstrated no benefit. He ultimately underwent an auditory brainstem implant (ABI) at age 3. His postoperative hearing and language outcomes are evolving, and the data are unavailable at this time.
Methods.
Institutional review board approval was obtained. Exome sequencing was performed in the proband and parents using the TruSeq Exome Library Prep Kit followed by 100 bp paired-end sequencing on a HiSeq 2500 instrument. We identified a compound heterozygote mutation in MASP1 in the propositus (c.1931C>T[p.Thr644Met] and c.49G>T[p.Ala17Ser]), each inherited from one parent, which was confirmed by Sanger sequencing. Both variants are rare in the ExAC Browser database of 60,706 unrelated individuals (3.049e-4 and 2.481e-05 allele frequencies, respectively), and the gnomAD beta browser of 126,216 exome sequenced and 15,136 whole-genome sequenced individuals, with no homozygotes reported. Both variants were predicted damaging when assessed with 2 separate integrative pathogenicity prediction tools that implement diverse annotations into a single overall prediction, i.e., Combined Annotation Dependent Depletion (CADD) score (33 and 22.7, respectively) and a random forest analysis with Integrating Molecular Heuristics and Other Tools for Effect Prediction (IMHOTEP; based on ENST00000296280 and ENST00000337774, respectively). Both variants are also conserved among species based on the genomic evolutionary rate profiling method. Last, p.Thr644Met and p.Ala17Ser are located within important protein domains in MASP1: p.Thr644Met affects a very conserved trypsin-like serine protease domain, likely affecting catalytic-proteolytic enzyme activity and p.Ala17Ser affects the CUB domain, which is often involved in oligomerization and/or recognition of substrates and binding partners. All of the preceding suggest these to be function-altering, deleterious, and disease-causal variants.
Mutations of this gene have been associated previously with 3MC syndrome (Carnevale, Mingarelli, Malpuech and Michels, or craniofacial-ulnar-renal syndrome).1 Affected individuals present with a range of anomalies that lead to abnormal facial/limb/vesicorenal development, cleft lip and/or palate, cognitive dysfunction, and craniosynostosis.2 Patients exhibit variable hearing and vestibular dysfunction. However, our patient does not have any other clinical features consistent with 3MC syndrome other than his SNHL and vestibular anomalies, expanding the clinical spectrum of MASP1 mutations.
Discussion.
Nearly 2–3 per 1,000 newborns suffer from hearing loss ranging from mild to profound in the United States each year.3 Children with profound SNHL are potentially considered for a CI or an ABI.4 However, current clinical imaging protocols are unable to consistently predict cochlear nerve status to guide surgeons' choice of auditory prosthesis.5 Improving preoperative imaging characterization is a subject of widespread research but has not yet reached clinical use.
The variability of hearing outcomes in children with abnormal cochleovestibular nerves receiving CIs/ABIs coupled with the current inability to predict their outcomes4,–,7 leads to children enduring multiple assessments and interventions. The length of time to determine which treatment will provide benefit often exceeds the sensitive periods for auditory development, delaying spoken language.
MASP1 encodes mannan-binding lectin serine protease 1 that is involved in complement activation. Previous studies show that MASP1 is involved to direct the migration of neural crest cells during embryonic development,2 and mutations cause a spectrum of human malformation syndromes as previously described, which demonstrate the involvement of MASP1 in facial, umbilical, and ear development during the embryonic period. Zebrafish morphants also develop pigmentary defects and severe craniofacial abnormalities.2
In this report, we expand the spectrum of phenotypic variability caused by MASP1 mutations and suggest that MASP1 screening should be considered in patients with nonsyndromic profound SNHL and abnormal cochleovestibular nerves.
Acknowledgments
Acknowledgment: The authors thank the family for participating in this study and Keri Ramsey for her help with sample collection.
Footnotes
↵* These authors contributed equally to this work as co–first authors.
Author contributions: Elina Kari: collection of data, interpretation of data, writing of the manuscript, and the corresponding author. Isabelle Schrauwen: collection of data, DNA sequencing, analysis of data, and writing of the manuscript. Lorida Llaci: DNA sequencing and sample preparation. Laurel M. Fisher: collection of data and interpretation of data. Marcus Naymik: bioinformatics. John L. Go: collection of data and interpretation of data. James A. Knowles: interpretation of data. Matthew J. Huentelman: interpretation of data. Rick A. Friedman: interpretation of data and final manuscript preparation.
Study funding: TGen, Translational Genomics Research Institute: this work was supported by private donations to TGen's Center for Rare Childhood Disorders. Rick Friedman: NIH R01 DC010856.
Disclosure: Dr. Kari has received travel funds from Cochlear Corporation and travel funds/speaker honoraria from Asan Medical Center. She also reports the following disclosures regarding her husband: he is a consultant for Otonomy, Inc.; has received research support from NIH/NIDCD; has stock in Otonomy, Inc.; and receives royalties from sales of Otiprio from Otonomy. Dr. Schrauwen has received research support from Arizona Alzheimer's Disease Core Center (ADCC). Ms. Llaci, Dr. Fisher, Dr. Go, and Mr. Naymik report no disclosures. Dr. Knowles has received research support from NIH/NIMH and the Della Martin Foundation. Dr. Huentelman has received research support from NIH/National Institute of Neurological Disorders and Stroke. Dr. Friedman is a co-founder for Otonomy Inc., which has no relationship to this publication. He also serves as a consultant for, has stock in, and receives royalties (from sales of Otiprio) from Otonomy, Inc.; has received travel funding/speaker honoraria from Cochlear Corporation and Asan Medical University; and has received research support from NIH. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was funded by the authors.
- Received December 17, 2016.
- Accepted in final form March 27, 2017.
- Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
References
- 1.↵
- 2.↵
- 3.↵CDC. Hearing loss in children. Available at: cdc.gov/ncbddd/hearingloss/data.html. Accessed January 1, 2016.
- 4.↵
- 5.↵
- Kari E,
- Go JL,
- Loggins J,
- Emmanuel N,
- Fisher LM
- 6.↵
- Birman CS,
- Powell HRF,
- Gibson WPR,
- Elliott EJ
- 7.↵
Letters: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Dr. Daniel Friedman and Dr. Sharon Chiang
► Watch
Related Articles
- No related articles found.