Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report

Abstract

BackgroundKBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported.Case presentationHere, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases.The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome.ConclusionsThis report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.

KBG syndrome: Common and uncommon clinical features based on 31 new patients

“…Pathogenic ANKRD11 mutations in patients presenting with an additional genetic anomaly have been reported, including a KMT2D mutation of Kabuki syndrome (Tunovic, Barkovich, Sherr, & Slavotinek, ), a de novo deletion of chromosome 9q (Xu et al, ), mutations in FLG (Ichthyosis vulgaris, MIM 146700), ARID1B (Coffin‐Siris syndrome, MIM #135900) and SLC6A 1 (Myoclonic‐atonic epilepsy, MIM #616421) in three different patients (Posey et al, ), a generalized epilepsy with febrile seizures due to SCN9A mutation (Alves et al, ). The use of exome sequencing will probably lead to the identification of additional associations, as shown by the study about co‐occurrences by Posey et al ().…”

Novel mutation of SCN9A gene causing generalized epilepsy with febrile seizures plus in a Chinese family

“…The first and second frequent phenotypes are febrile seizures, where generalized tonic-clonic seizures (GTCS) with fever occur between 3 months and 6 years, and febrile seizures plus (FS+), in which attacks with fever extend beyond 6 years or afebrile GTCS occur, respectively. The other phenotypes include FS/ FS+ with absence, myoclonic, atonic, or focal seizures [11]. In our study, the proband experienced FS and FS+ with absence while his father and aunt only had febrile seizures, probably due to the incomplete penetrance and/or the phenotypic heterogeneity.…”

“…Cen et al reported a small pedigree diagnosed as GEFS+ with a heterozygous mutation (Q10R) in SCN9A gene without SCN1A mutation [4]. In 2019, a heterozygous mutation in the SCN9A gene, p.(Lys655Arg), in two sisters from a nonconsanguineous family who presented GEFS+ was detected [11]. Actually, SCN9A variant is often mentioned as a genetic modifier in SCN1A mutation-associated epilepsy.…”

Branding of subjects affected with genetic syndromes of severe short stature in developing countries

“…Since then, we never used that term again and encourage all physicians to do the same. The widespread insensibility concerning the use of the term ‘dwarf’ or similar40–49 underscores the present need of finally eliminating such terms from the medical lexicon. To this regard, it is relevant to quote at this time Dr David W Smith, the father of modern dysmorphology.…”