ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000016.9) (NC_000016.10)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: KBG SYNDROME; KBGS
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

KBG syndrome is characterized by macrodontia of the upper central incisors, distinctive craniofacial findings, short stature, skeletal anomalies, and neurologic involvement that includes global developmental delay, seizures, and intellectual disability (from OMIM #148050). It has been suggested that KBG syndrome and 16q24.3 microdeletion syndrome are distinct clinical entities, though there is overlap within their clinical features. Miyatake et al. (2013) (PMID: 23463723) summarize the proposed differences between the two as such: "...the detailed manifestation of neurological involvement looks somehow different. In 16q24.3 microdeletion syndromes, intellectual impairment is relatively mild and autistic spectrum disorders are frequently observed [Willemsen et al., 2010; Isrie et al., 2012]. On the other hand, in KBG syndrome, intellectual disability ranges from mild to severe, and common behavioral disturbances are hyperactivity, attention deficit or easy frustration rather than autistic features [Brancati et al., 2006]. At this point, our patient and the familial patients reported by Sacharow et al. [2012] are very significant in that they have 16q24.3 microdeletion, but their neurological symptoms are closer to those of KBG syndrome. Haploinsufficiency of ANKRD11 has to be confirmed in 16q24.3 microdeletion syndrome to clarify whether these two syndromes are different. Clinical differences might be due to the ambiguous diagnostic criteria for KBG syndrome or to additional deleted gene(s) being associated with other features in 16q24.3 microdeletion syndrome. To resolve this, it is necessary to study further patients with these two syndromes." These authors also discuss their own patient with a clinical diagnosis of KBG syndrome and a deletion including a portion of ANKRD11 (along with other genes) and speculate on an additional difference between the two proposed clinical entities: "The unique finding of our case is hypoplasia of cerebellar vermis, especially in the lower segment. The deleted region in 16q24.3 of our patient did not contain any known causative genes for cerebellar hypoplasia. In the literature review, there are two patients with KBG syndrome that had hypoplastic lower segment of cerebellar vermis. One of them had difficulty in keeping the standing position or walking because of cerebellar ataxia [Zollino et al., 1994]. Thus, we speculate that hypoplasia of the cerebellar vermis, especially in the lower segment, is a rare complication of KBG syndrome. Since there has not been any case of 16q24.3 microdeletion syndrome with this finding, it might be one of the hallmarks for KBG syndrome."

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity