Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search

Abstract

Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.

Keywords: ANKRD11 gene; Growth hormone treatment; Growth plate development; Hotspot variants; KBG syndrome; Short stature.

Fig. 1

Molecular spectrum of ANKRD11 variants. A total of 583 ANRKD11 (likely) pathogenic variants were collected through literature review and ClinVar database. ANKRD11 variants were shown by frameshift, nonsense, missense, splice and inframe deletion, respectively. ANK: ankyrin repeat domain, RD1: repression domain 1, AD: activation domain, RD2: repression domain 2

Fig. 2

The percentage of different types of ANKRD11 variants located in different functional domains. The pie chart indicates the percentage of variants within different domains. 10 X 10 dot plot represents the percentage of different variant types. The column shows the the proportion of five mutation types within different domains of ANKRD11. ANK: ankyrin repeat domain, RD1: repression domain 1, AD: activation domain, RD2: repression domain 2

Fig. 3

Frequency of ANKRD11 variants in a total of 838 KBGS patients (A) and ANKRD11 allele frequency in general population (B). ANKRD11 allele frequency below 1% in general poulation was obtained from gnomAD (http://gnomad-sg.org/). The abscissa represents the full-length amino acid sequence of ANKRD11, and the ordinate represents the frequency

Fig. 4

Distribution of gender and height SDS of patients having ANKRD11 variants (A) and comparison of height SDS of patients having ANKRD11 variants within different domain (B) or having different ANKRD11 variant types (C). ANK: ankyrin repeat domain, RD1: repression domain 1, AD: activation domain, RD2: repression domain 2

Fig. 5

Disease-causing genes associated with short stature through affecting the endochondral ossification of epiphyseal growth plate. The ANKRD11 gene may be implicated in this process as a transcription regulator. RZ: resting zone, PZ: proliferative zone, PHZ: prehypertrophic zone, HZ: hypertrophic zone