Natural history of KBG syndrome in a large European cohort

Abstract

KBG syndrome is characterised by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterise natural history of KBG syndrome. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array-CGH and NGS approach investigated both genomic CNVs/SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while OFC (median value: −0.88 SD at birth) normalised over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia, and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ENT evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

Documentation and prevalence of prenatal and neonatal outcomes in a cohort of individuals with KBG syndrome

“…The prenatal and neonatal results of our cohort mirror those reported in past KBG cohorts. In a previous Northern European cohort of 49 individuals, 16% of participants had congenital heart defects, including ASD, VSD, and valvular insufficiencies (Loberti et al, 2022). 10.2% of participants had arachnoid cysts, 23% of participants had an enlarged cisterna magna, and other participants had periventricular nodular heterotopia.…”

“…Feeding difficulties were commonly seen in this cohort. In terms of prenatal findings, 28.5% had antenatal ultrasound abnormalities, including nuchal translucency, polyhydramnios, and intrauterine growth restriction (Loberti et al, 2022). Another cohort of 45 individuals reported 31.3% with feeding difficulties, 9% with congenital heart defects, and 28% of participants with cryptorchidism.…”

“…A separate literature review was conducted in order to compare pregnancy outcomes in our cohort to those in other published KBG syndrome cohorts. PubMed was searched for studies that included the terms “KBG + prenatal,” “KBG + neonatal,” “KBG + pregnancy,” “KBG + utero,” and “KBG + newborn.” Studies were included if they presented prenatal or neonatal phenotypes of confirmed KBG syndrome, giving a total of four papers used to compare our results (Brancati et al, 2006; Loberti et al, 2022; Low et al, 2016; Morel Swols & Tekin, 2018).…”

Deletion of first noncoding exon in ANKRD11 leads to KBG syndrome

“…Prior studies have noted that haploinsufficiency is the likely pathogenic mechanism in these cases based on the tightly regulated abundance of ANKRD11 during the cell cycle (Walz et al, 2015). Moreover, molecular analysis of cohorts of patients with KBG syndrome have found that the majority of ANKRD11 pathogenic variants are frameshift and nonsense variants leading to a loss‐of‐function, and presumably, haploinsufficiency as well (Gnazzo et al, 2020; Goldenberg et al, 2016; Loberti et al, 2022; Low et al, 2016; Parenti et al, 2021; Scarano et al, 2019). Recenty, functional studies performed on ANKRD11 missense variants found these decreased ANKRD11 stability and transcriptional activity, further supporting haploinsufficiency as a pathologic mechanism for KBG syndrome (de Boer et al, 2022).…”

KBG syndrome: Clinical features and molecular findings in seven unrelated Korean families with a review of the literature

“…Seizures occurred in three patients (3/8, 37.5%), and abnormal EEG findings were observed in two patients (2/8, 50%), including one who did not show clinical findings of seizure. Prior to the recently published European large‐scale cohort paper (Loberti et al, 2022 ), the comorbidity rate of brain malformations in patients with KBG syndrome was not known precisely. It reported that 32 out of the total 49 cohort patients underwent brain MRI, and cerebral abnormalities were found in more than half of them (18/32, 56.3%).…”