Intellectual Disability via the MYT1L Gene

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70) and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD).

Deficiency of MYT1L hypothetically impairs neural development, thereby leading to mental retardation 39 (MRD39). The clinical features of MRD39 may include (but may not be limited to) severe intellectual disability, developmental delay, speech and language delay, motor delay, obesity, brachycephaly, microcephaly, neonatal hypotonia, hyperlaxity, seizures, feeding difficulties, sleep disturbances, strabismus, behavioral abnormalities such as autism, stereotypic movements, hyperactivity, attention-deficit, aggressiveness, and variable facial dysmorphism including short, square-shaped face, broad forehead, upslanted palpebral fissures, narrow eyes, broad base and bridge of the nose, upturned nose, large ears and large mouth (de Ligt et al. 2012. PubMed ID: 23033978; De Rocker et al. 2015. PubMed ID: 25232846; Mayo et al. 2015. PubMed ID: 26240977). Of note, MYT1L has also been associated with schizophrenia (Stevens et al. 2011. PubMed ID: 21990140).

MRD39 is an autosomal dominant disorder, caused by pathogenic variants (primarily de novo) in human Myelin transcription factor 1-like gene (MYT1L). MYT1L maps to chromosome 2p25.3 and consists of 20 coding exons that translate an 1186 amino acid polypeptide. MYT1L contains one MYT domain and six to seven zinc-finger binding motifs and hypothetically acts as a neural-lineage specific transcription factor (Vierbuchen et al. 2010. PubMed ID: 20107439; Pang et al. 2011. PubMed ID: 21617644). Although small frameshift deletions, missense, nonsense and splice variants have been reported in MYT1L, the majority of the pathogenic variants are gross deletions/duplications and complex rearrangements involving MYT1L (Human Gene Mutation Database).

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016. PubMed ID: 26503795). Analytical sensitivity should be high because all single nucleotide pathogenic variants reported within this gene to date are detectable by sequencing. However, the majority of reported pathogenic variants (37/55) involving MYT1L are gross deletions/duplications (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the MYT1L gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.