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Abstract Details

A case report of resolving an uncertain variant in CHRN1B as pathogenic leading to Congenital Myasthenic Syndrome type 2C.
Neuromuscular and Clinical Neurophysiology (EMG)
P1 - Poster Session 1 (8:00 AM-9:00 AM)
The patient was born at 37 weeks gestation. There were polyhydramnios and a breech presentation at delivery. Early respiratory failure necessitated intubation and mechanical ventilation. Examination demonstrated retrognathia, contractures, ptosis, generalized hypotonia and weakness. Creatine kinase was 671 units/L (57-374 units/L).  Metabolic testing, myotonic dystrophy testing, and chromosomal microarray were normal. Brain MRI was unremarkable. Repetitive nerve stimulation at 3Hz demonstrated a >30% decrement in weak muscles. Whole genome sequencing was performed.
We resolved a variant as pathogenic in a newborn with severe weakness and compound heterozygous mutations in CHRNB1 that codes for acetylcholine receptor beta subunit resulting in congenital myasthenic syndrome type 2C (CMS2C).
The paternal intronic deletion c.1218-9_1218-7, classified as a variant of uncertain significance, is predicted to reduce the quality of the natural splice acceptor site in intron 9 allowing abnormal splicing. The maternally inherited 2Kb microdeletion at 17p13.1, includes the 3' portion of CHRNB1 gene. Patient’s presentation is recessive since neither parent is affected. Both deletions likely lead to unstable mRNA for the acetylcholine receptor beta subunit and severely reduced muscle nicotinic acetylcholine receptor. Patient was started on pyridostigmine with notable improvement though still severely weak.
CMS2C is a rare neonatal onset disorder associated with respiratory failure and poor feeding due to acetylcholine receptor deficiency and concordant abnormalities on electrophysiologic studies all expected to be secondary to deficiency of acetylcholine receptor at the neuromuscular endplate. Weakness is static with partial response to acetylcholinesterase inhibitors. There are few than 4 reports in the literature of biallelic mutations in the CHRNB1 gene. We resolved a reported variant as pathogenic. This will expedite diagnosis, initiation of therapy, and facilitate discussion of prognosis for future patients with this mutation.
Zurisadai Gonzalez Castillo, MD (University of California, Irvine)
Dr. Gonzalez Castillo has nothing to disclose.
Simon Kayyal, MD Dr. Kayyal has nothing to disclose.
Neda Zadeh, MD (CHOC Children's Hospital and Genetics Center) Dr. Zadeh has nothing to disclose.
Julian Thomas, MD (CHOC Physician Subspecialty Faculty) Dr. Thomas has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen.