Five Truncating Germline Mutations in MSL2 in Patients with Neurodevelopmental Disorders

Neurodevelopmental disorders (NDDs) are a diverse group of conditions affecting the development of the nervous system. NDDs manifest as array of phenotypes including intellectual disability, motor delays, and behavioral abnormalities. Recent studies have identified truncating mutations in the MSL2 gene. MSL2 gene is a part of the male-specific lethal (MSL) complex playing a key role in chromatin regulation. Premature truncating variants disrupt normal MSL2 function and are associated with syndromes characterized by autism spectrum disorder (ASD), intellectual disability (ID), and other neurodevelopmental and behavioral manifestations. Below, we present five cases of truncating mutations in MSL2, identified and compiled using Adenine AI: Organized Evidence for Medical Genetics, that have been linked to distinct phenotypes, including lack of coordination, epilepsy, and dysmorphic features.

1. Female/13 years

   • Age/Sex: 13-year-old female
   • Phenotype: Global developmental delay, ASD, ADD, visual and language processing disorder, OCD, high myopia, hypermobile EDS
   • Zygosity: Heterozygous for de novo MSL2 truncating variant
   • Mutation: MSL2:p.Thr217AspfsX2
   • PMID: 34230636

2. Female/6 years

   • Age/Sex: 6-year-old female
   • Phenotype: ASD, developmental delay (DD), hypotonia, and feeding difficulties
   • Zygosity: De novo truncating mutation in MSL2
   • Unique characteristic: Hypotonia with mild dysmorphisms such as down-slanting palpebral fissures and flat midface.
   • Mutation: MSL2:c.796_797delCT (p.Leu266ValfsX5)
     PMID: 33860439

3. Male/11 year

   • Age/Sex: 11-year-old male
   • Phenotype: Global developmental delay, intractable seizures, abnormal MRI findings, aggressive behavior
   • Zygosity: De novo truncating mutation in MSL2
   • Unique characteristic: Extensive brain abnormalities, including white matter atrophy and cystic changes.
   • Mutation: MSL2:c.1047_1050del (p.Ser349Argfs*23)
     PMID: 33860439

4. Female/16 year

   • Age/Sex: 16-year-old female
   • Phenotype: Central hypotonia, exercise intolerance, and difficulty swallowing
   • Zygosity: Heterozygous truncating mutation in MSL2
   • Unique characteristic: Required wheelchair assistance due to severe motor weakness, with no facial dysmorphisms.
     PMID: 33860439
   • Mutation: MSL2:c.67G>T (p.Gly23Ter) 

5. Female/4 months

   • Age/Sex: 4-months-old female
   • Phenotype: Severe neuromuscular impairment, hypotonia, respiratory support required
   • Zygosity: Truncating mutation in MSL2
   • Unique characteristic: Epilepsy onset within 24 hours of birth, significant EEG abnormalities including hypsarrhythmia.
   • Mutation: MSL2:c.778delA (p.Ile260Ter)
     PMID: 38815585

Conclusion:
The truncating mutations in MSL2 identified in these cases suggest a distinct neurodevelopmental syndrome characterized by a range of motor and cognitive impairments, behavioral issues, and dysmorphisms. Early identification of these mutations through genomic sequencing provides critical insights into managing and diagnosing patients with these rare disorders.