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
18992374 Lo-Castro et al (2009) identified a de novo 1.1 Mb deletion of SOX11 using aCGH in a 7 year old girl with intellectual disability, autism, microcephaly, dysmorphic features, strabismus, language delay, and hypotonia. Given that SOX11 was the only gene in the deletion, and no other CNVs were observed in the array, the authors propose haploinsufficiency of SOX11 as causative.
26543203 Hempel et al (2016) characterized clinical findings of 10 unrelated individuals with SOX11 alteration and a clinical phenotype that overlaps Coffin-Siris syndrome. This study included seven individuals with deletion of SOX11 and three individuals with de novo SOX11 mutation. Individuals with deletion of 2p25.2 including SOX11 were identified through the DECIPHER collaboration. Two of the deletions were isolated to SOX11 (Cases 1 and 7), the others included other genes. Case 1 had a de novo 2.6 Mb deletion and Case 7 had a 1.2 Mb deletion. Parents were not available for follow up for Case 7. Both individuals had motor delays, speech delay, and 5th finger clinodactyly. For the remaining deletion cases, two were de novo (cases 2 and 4), one was unknown, not maternally inherited (case 3), one was paternally inherited, with reported epilepsy, ID and speech delay (case 5) and one was of unknown inheritance (case 6). Three individuals with mutation of SOX11 were identified from either the DDD study (2 patients; data freeze of 1133 children) or by exome sequencing in another large British study. One nonsense and two missense mutations were characterized, all were de novo. All mutations were confirmed by Sanger sequencing. Functional studies: In vitro functional analysis of two missense variants using a luciferase reporter assay showed stable protein expression with reduced ability to activate GDF5 reporter expression compared to wild-type. Functional analysis in vivo by morpholino knockdown in xenopus laevis showed a microcephalic phenotype in morphants relative to control morpholino-injected embryos. Based on this collection of findings, the authors propose that haploinsufficiency of SOX11 is responsible for a neurodevelopmental phenotype and microcephaly.
24886874 Tsurusaki et al (2014) performed whole exome sequencing of patients with a diagnosis of Coffin-Siris syndrome and identified two de novo missense mutations in two unrelated individuals with features including dysmorphic facial features, microcephaly, growth deficiency, hypoplastic fifth toe nails and mild intellectual disability. The authors classified these mutations as causing a mild form of Coffin-Siris syndrome. In vitro functional studies demonstrated reduced transcriptional activity, consistent with a loss-of-function impact. The authors suggest that mutations in SOX11 are a rare cause of a milder Coffin-Siris syndrome phenotype.

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.