Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients

Abstract

BackgroundKBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involvingANKRD11cause KBG syndrome, but no genotype–phenotype correlation has been reported.Methods67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a ‘phenotypical score’ were used to perform a genotype–phenotype correlation in 340 patients from our cohort and the literature.ResultsNeurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions.ConclusionWe present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype–phenotype correlation between some KBG features and specificANKRD11variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

High Performance of a Dominant/X-Linked Gene Panel in Patients with Neurodevelopmental Disorders

“…For 25 different genes, pathogenic/likely pathogenic variants were detected in more than one patient ( Table S4 ). Among those, five de novo pathogenic variants were identified in ANKRD11, causing KBG syndrome, characterized by macrodontia of the upper central incisors, characteristic facial features, short stature, developmental delay/intellectual disability, and behavioral issues [ 36 ].…”

Functional investigation of a novel ANKRD11 frameshift variant identified in a Chinese family with KBG syndrome

“…The molecular etiology of KBG syndrome was not discovered until 2011 when ANKRD11 mutations were identified through the application of next-generation high-throughput DNA sequencing technology in clinical and molecular genetic studies [ 3 ]. Currently, ClinVar database has recorded more than 450 pathogenic or likely pathogenic ANKRD11 variants, predominantly frameshift and nonsense variants, suggesting that the number of KBG syndrome patients far exceeds the previously reported 340 cases [ 4 ]. Statistically, among the 253 KBG syndrome patients harbouring ANKRD11 variants, 100 %, 80 %, 77 %, 52 %, 38 % and 29 % exhibited craniofacial anomalies, macrodontia of the upper central incisors, intellectual diability, short stature, hearing loss, and congenital heart defect, respectively [ 5 ].…”

Epileptic dyskinetic encephalopathy in KBG syndrome: Expansion of the phenotype

“…KBG syndrome (OMIM 158050), named according to the initials of the first three patients K, B and G, was first described in 1975. Classic features of KBG syndrome include characteristic dysmorphisms, macrodontia of the upper incisors, short stature, and developmental impairment [1] , [2] , [3] . The gene identified in KBG syndrome is ANKRD11 (encoding ankyrin repeat domain 11) and plays an important role in neurogenesis, transcription regulation and epigenetic processes [4] .…”