MID1 was first reported in relation to X-linked Opitz G/BBB syndrome in 1997 (Quaderi et al. PMID: 9354791). Opitz G/BBB syndrome is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, laryngotracheoesophageal defects, cleft lip/palate, congenital heart defects, and midline defects of the brain, including agenesis of the corpus callosum and cerebellar vermis agenesis or hypoplasia. Intellectual disability/developmental delay (ID/DD) are observed in about 15%-50% of affected males. A review of the clinical phenotypes of 85 affected males with MID1 variants showed that about one-third have ID/DD (PMID: 26788540). Among the 16 cases of genetic evidence curated here, 6 have ID/DD, 7 do not have ID/DD, and 3 have no information. Female patients usually present with isolated hypertelorism. The disease mechanism is loss of function. In summary, MID1 is definitively associated with X-linked Opitz G/BBB syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 21, 2018 (SOP version 5).
MID1 was first reported in relation to X-linked Opitz G/BBB syndrome in 1997 (Quaderi et al., PMID: 9354791). Opitz G/BBB syndrome is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, laryngotracheoesophageal defects, cleft lip/palate, congenital heart defects, and midline defects of the brain, including agenesis of the corpus callosum and cerebellar vermis agenesis or hypoplasia. Intellectual disability/developmental delay (ID/DD) are observed in about 15%-50% of affected males. A review of the clinical phenotypes of 85 affected males with MID1 variants showed that about one-third have ID/DD (PMID: 26788540). Female patients usually present with isolated hypertelorism.
Sixteen variants (nonsense, frameshift, missense) that have been reported in 16 probands in four publications (PMIDs: 11030761, 12833403, 15121778, 17221865) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Among the 16 cases curated here, 6 have ID/DD, 7 do not have ID/DD, and 3 have no information. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by a Mid1-null mouse model (PMID: 20181585).
In summary, there is definitive evidence supporting the relationship between MID1 and X-linked Opitz G/BBB syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 21, 2018 (SOP Version 5).
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