Compound Heterozygous CHAT Gene Mutations of a Large Deletion and a Missense Variant in a Chinese Patient With Severe Congenital Myasthenic Syndrome With Episodic Apnea

Abstract

Congenital myasthenic syndromes (CMSs) are a group of inherited disorders caused by genetic defects in neuromuscular junctions. Mutations in CHAT, encoding choline acetyltransferase, cause congenital myasthenic syndrome with episodic apnea (CMS-EA), a rare autosomal recessive disease characterized by respiratory insufficiency with cyanosis and apnea after infections, fever, vomiting, or excitement. To date, no studies have reported deletions comprised of multiple exons. Here, using next generation sequencing, we identified compound heterozygous mutations, namely a large maternally inherited deletion, including exons 4, 5, and 6, and a paternally inherited missense variant (c.914T>C [p.Ile305Thr]) in CHAT in a Chinese patient with a severe phenotype of CMS-EA. Furthermore, the large deletion was also validated by real-time fluorescence quantitative polymerase chain reaction. The patient was a 10-month-old boy, who presented with a weak cry and feeding difficulties soon after birth, ptosis at 4 months old, episodic apnea after fever at 9 months old, and respiratory insufficiency with cyanosis and apnea that required intubation after a respiratory tract infection at 10 months old. Unfortunately, he died in the Pediatric Intensive Care Unit soon after hospitalization. The patient’s elder sister had similar clinical manifestations, and she died prior to the age of 2 months old without a diagnosis. Genotype-phenotype correlation analysis revealed that loss-of-function mutations in exons 4–6 of CHAT might cause more severe CMS-EA. To our knowledge, this is the first study to show compound heterozygous CHAT mutations consisting of a large deletion and missense mutation in a patient with CMS-EA.

Vocal Cord Paralysis and Feeding Difficulties as Early Diagnostic Clues of Congenital Myasthenic Syndrome with Neonatal Onset: A Case Report and Review of Literature

“…In Table 1 we summarized cases of congenital myasthenic syndrome with neonatal onset previously described and compared them to our case. The literature reported one hundred fifty-five neonatal cases before our case, from 1980 to March 2022 [ 4 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. Therefore, of 156 neonates with congenital myasthenic syndrome, nine (5.8%) had vocal cord paralysis, whereas 111 (71.2%) had feeding difficulties.…”

A multidimensional computational exploration of congenital myasthenic syndrome causing mutations in human choline acetyltransferase

“…Additionally, CMS caused by CHAT is classified as a presynaptic form of CMS, and those are estimated to account for only a small percentage of all CMS cases. For example, in Asia, it has been reported in only five families 13,18,49,50 . When the Mayo Clinic conducted a cohort study of CMS patients between 1988 and 2006, only 13 of the 248 identified CMS patients had a CHAT genetic defect 15 .…”

“…We sought to evaluate our sifting criteria before proceeding further. To do so, we collected all 36 CHAT SNPs associated with CMS that have been reported so far 9‐14,16‐20,49,50,52‐54 and subjected them to our filtering process. In the first step, 89% (32) mutations were predicted to be deleterious, which is much higher than the 26% we obtained when filtering the 334 unassigned missense mutations.…”

Central Apneas Due to the CLIFAHDD Syndrome Successfully Treated with Pyridostigmine

“…The most crucial differential diagnosis remains the exclusion of CMS, especially congenital myasthenic syndrome with episodic apnea (CMS-EA), caused by mutations in the CHAT gene, encoding choline acetyltransferase, or the RAPSN gene, encoding a postsynaptic protein, connecting and stabilizing acetylcholine receptors (AChR) at the neuromuscular junction [ 4 ]. Episodes of apnea and respiratory insufficiency are the hallmarks of CHAT pathogenic variants.…”