ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
27824329 Wang et al. (2016) report a de novo nonsense variant (p.Gln848*) in MYT1L identified in a male with autism, developmental delay, sleep problems, attention problems, anxiety, febrile seizures, a "pigeon-toed" gait, and motor tics. No comment was made on whether or not this individual was obese. The individual was studied as part of a larger cohort of 1543 Chinese individuals with autism spectrum disorders (ASD) sequenced for 189 ASD risk genes determined by the authors. The authors note that MYT1L showed no evidence of rare, likely-gene-disruptive variants in ExAC. The authors also note that an additional instance of a de novo, likely-gene-disruptive variant was observed in the Autism Sequencing Cohort (ASC), and additional missense variants (2 total) were also observed in the ASC and in the Simons Simplex Collection (SSC).
23033978 de Ligt et al. (2012) performed trio-based exome sequencing on 100 individuals with severe intellectual disability, defined as having an IQ below 50. In Trio 92 (discussed in the supplementary material) they identified a de novo splice site variant in MYT1L (NM_015025.2 c.2636+1G>A). This variant was identified in a female patient described as follows: "This female was born after a normal pregnancy and delivery with a high birth weight (4750 grams, >+2 SD). She had neonatal hypotonia and feeding difficulties. Parents had noticed a developmental delay since the age of 6 months. She could walk without support at the age of 28 months and started to speak her first single words at the age of 3.5 years. She made stereotypic movements. At the age of 12 years she had an IQ of about 45 and showed autistic features. Upon physical examination at the age of 12 years and 8 months she had normal growth parameters and mild facial dysmorphism, including a broad base and bridge of the nose and a large mouth. SNP array analysis, Angelman methylation studies, UBE3A, and a metabolic screen were normal."
25232846 de Rocker et al. (2015) report two de novo LOF variants (c.2636+1G>A (NM_015025.2) and NM_015025.2: c.1917T>G ; p.(Tyr639*)) in individuals with intellectual disability (patients 14 and 15, respectively). Patient 14 is described in the supplementary material as having: a history of neonatal hypotonia and feeding difficulties; developmental delay since the age of 6 months; stereotypic movements; an IQ of about 45 (at the age of 12 years); autistic features; normal growth parameters (at age 12 years); and mild facial dysmorphism. Patient 15 is described as having: history of developmental delay; IQ of 50 at 9 years of age; autism spectrum disorder; weight at the 90th percentile; and mild dysmorphic features.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.