ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
21782149 Sirmaci et al. 2011: In a study of ten families from Turkey and Italy with a clinical diagnosis of KBG syndrome, the authors identified a heterozygous variant (c.7570-1G>C (p.Glu2524_Lys2525del) in the ANKRD11 gene by whole exome sequencing segregating with the phenotype within a multiplex family and a heterozygous de novo variant (c.2305delT (p.Ser769GlnfsX8) in ANKRD11 in a simplex family. Sanger sequencing of ANKRD11 for the remaining 8 families revealed three additional heterozygous truncating mutations in three simplex families, including one nonsense mutation, c.7189C>T (p.Gln2397X). All of these were determined to be de novo. All five ANKRD11 mutations were negative in ethnicity-matched controls. Sanger sequencing as well as CNV analysis of ANKRD11 via quantitative PCR remained negative in the five other probands.
23494856 Khalifa et al. 2013: The authors describe a 2 year-old male with developmental delay and mutliple anomalies, including: distinctly round facies, epicanthic folds, hypertelorism, broad arched eyebrows with synophrys, a flat nasal bridge, a relatively small nose with a bulbous tip, hypertelorism, striking macrodontia, brachydactyly, partial syndactyly, and a history of patent foramen ovale (PFO), umbilical hernia, hypospadias with chordee, and penile?scrotal fusion. Height was said to be at the 10th percentile. Genomic microarray was significant for a 154?kb deletion within 16q24.3, limited to ANKRD11. The patient's mother was found to be a mosaic carrier of this deletion. She has a history of abnormal dentition with malposition and extra teeth requiring extraction, macrodontia, brachydactyly, and partial 2-3 toe syndactyly. She reported a history of learning difficulties, but not overt developmental delay, and was able to graduate from college. The authors did not specify whether a diagnosis of KGB syndrome was considered before the micorarray result was made available, or whether it was determined that their symptoms fit the clinical spectrum of KGB in light of the microarray results.
21654729 Isrie et al. 2012: The authors report two patients with cognitive impairment, short stature and dysmorphic features and microdeletions involving ANKRD11. One of these microdeletions was a 138-kb intragenic deletion that minimally included exons 3?12; exons 2 and 13 were located between the last non-deleted and the first deleted probes, but exon 1 was not in the deletion. Two other variants were identified in the patient and his healthy father, a 500-kb duplication at 2q37.3 and a 223-kb duplication in the PAR2 region of the Y chromosome and were considered by the authors to be non-pathogenic. This patient was described as a 19 year old male with short stature, dysmorphic features including high and broad forehead, cowlicks, slightly deep-set eyes, mild synophrys, a broad nose with a short columella, protruding ears, a broad mouth and a prominent chin, and shortened metacarpals of the fourth and fifth digits on his left hand. A skeletal survey showed short metacarpals and short fifth middle phalanges. He was said to have a history of developmental delay and attention deficit disorder. No comment was made on his dentition. The authors did not describe these individuals as having KBG syndrome, but instead implied that they had a distinct 16q24.3 microdeletion syndrome.

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.