A de novo frameshift variant of ANKRD11 (c.1366_1367dup) in a Chinese patient with KBG syndrome

Abstract

Background KBG syndrome is a rare autosomal dominant genetic disease mainly caused by pathogenic variants of ankyrin repeat domain-containing protein 11 (ANKRD11) or deletions involving ANKRD11. Herein, we report a novel de novo heterozygous frameshift ANKRD11 variant via whole exome sequencing in a Chinese girl with KBG syndrome. Case presentation A 2-year-2-month-old girl presented with a short stature and developmental delay. Comprehensive physical examinations, endocrine laboratory tests and imaging examination were performed. Whole‐exome sequencing and Sanger sequencing were used to detect and confirm the variant associated with KBG in this patient, respectively. The pathogenicity of the variant was further predicted by several in silico prediction tools. The patient was diagnosed as KBG syndrome with a short stature and developmental delay, as well as characteristic craniofacial abnormalities, including a triangular face, long philtrum, wide eyebrows, a broad nasal bridge, prominent and protruding ears, macrodontia of the upper central incisors, dental crowding, and binocular refractive error. Her skeletal anomalies included brachydactyly, fifth finger clinodactyly, and left-skewed caudal vertebrae. Electroencephalographic results generally showed normal background activity with sporadic spikes and slow wave complexes, as well as multiple spikes and slow wave complexes in the bilateral parietal, occipital, and posterior temporal regions during non-rapid-eye-movement sleep. Brain MRI showed a distended change in the bilateral ventricles and third ventricle, as well as malformation of the sixth ventricle. Whole exome sequencing revealed a novel heterozygous frameshift variant in the patient, ANKRD11 c.1366_1367dup, which was predicted to be pathogenic through in silico analysis. The patient had received physical therapy since 4 months of age, and improvement of gross motor dysfunction was evident. Conclusions The results of this study expand the spectrum of ANKRD11 variants in KBG patients and provide clinical phenotypic data for KBG syndrome at an early age. Our study also demonstrates that whole exome sequencing is an effective method for the diagnosis of rare genetic disorders.

Ocular manifestations in a cohort of 43 patients with KBG syndrome

“…Gnazzo et al (2020) reported a 13% prevalence of strabismus, whereas Choi et al (2023) reported a single case of strabismus among their cohort. Chen et al (2021) and Nizette and Duchesne, (2021) both reported isolated cases of patients with KBG syndrome having binocular refractive errors, with the latter also reporting concurrent bilateral corneal clouding. Finally, Novara et al (2017) reported four cases of astigmatism and two cases of myopia among their cohort.…”

“…Although ophthalmological findings have been reported in some cases of KBG syndrome (Brancati et al, 2006; Chen et al, 2021; Nizette & Duchesne, 2021; Novara et al, 2017), there is currently a lack of research that estimates the incidence of visual problems among those with diagnosed KBG syndrome, or determines if there is a link between KBG syndrome and visual impairments. Our analysis of visual impairments in patients with KBG syndrome hints that a significant relationship may exist between the two.…”

Ocular Manifestations in a Cohort of 43 Patients with KBG Syndrome

“…Although ophthalmological findings have been reported in some cases of KBG syndrome [2,11,17,18], there is currently a lack of research that estimates the incidence of visual problems among those with diagnosed KBG syndrome, or determines if there is a link between KBG syndrome and visual impairments. Our analysis of visual impairments in patients with KBG syndrome hints that a significant relationship may exist between the two.…”

Dyggve-Melchior-Clausen Syndrome Caused by a Novel Frameshift Variant in a Japanese Patient

“…All SEMDs are characterized by short stature. However, ID is only observed in some patients with SEMDs, including DMC, Faden-Alkuraya type (RSPRY1 variant) [Faden et al, 2015], Liberfarb type (PISD) [Girisha et al, 2019;Zhao et al, 2019], Camera-Genevieve type (NANS) [Geneviève et al, 2005;van Karnebeek et al, 2016], Krakow type (SIK3) [Csukasi et al, 2018], KBG syndrome (ANKRD11) [Chen et al, 2021], and SEMD-HL (AIFM1) [Miyake et al, 2017]. Patients with DMC have unusual features such as coarse face, microcephaly, and lacy appearance in the iliac crests on radiography.…”