This case expands the molecular spectrum of KBG syndrome and highlights the importance of genomic testing in children presenting with developmental delay, learning difficulties, and subtle dysmorphic features, particularly when the diagnosis remains uncertain during early childhood.
Abstract
KBG syndrome is a rare autosomal dominant neurodevelopmental disorder caused by pathogenic variants
in the ANKRD11 gene. The clinical presentation is highly variable and may include characteristic craniofacial
features, developmental delay, learning disabilities, behavioral abnormalities, and growth impairment. Here
we describe a Lebanese female patient who was followed for 11 years because of failure to thrive,
developmental delay, attention deficit, behavioral difficulties, and persistent learning disabilities. Longitudinal follow-up documented gradual neurocognitive improvement with multidisciplinary interventions and
pharmacological treatment for attention and behavioral difficulties. Whole Exome Sequencing (WES),
performed at the age of 11 years, identified a novel heterozygous frameshift pathogenic variant in the
ANKRD11 gene (p.Tyr808fs), confirming the diagnosis of KBG syndrome. To our knowledge, this is the first
reported Lebanese patient carrying this specific ANKRD11 variant. This case expands the molecular
spectrum of KBG syndrome and highlights the importance of genomic testing in children presenting with
developmental delay, learning difficulties, and subtle dysmorphic features, particularly when the diagnosis
remains uncertain during early childhood.
Background KBG syndrome (KBGS) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous pathogenic variants in ANKRD11. It is characterized by developmental delay, intellectual disability, behavioral difficulties, macrodontia, craniofacial dysmorphism, short stature, and skeletal anomalies. Objectives To describe the clinical, radiological, and molecular findings of Saudi patients with molecularly confirmed KBGS and compare their presentation with reported features in the literature. Methods We conducted a retrospective case series at King Faisal Specialist Hospital and Research Centre, Riyadh, between January 2002 and December 2024. Clinical, dysmorphological, developmental, behavioral, family history, neuroimaging, and molecular data were reviewed for three pediatric patients with confirmed ANKRD11-related KBGS. Results All patients demonstrated core features of KBGS, including intellectual disability, speech and motor delay, learning difficulties, and behavioral manifestations such as autism spectrum features or aggression. Common dysmorphic findings included long philtrum and prominent ears in all patients, with a triangular face, macrodontia, and synophrys observed in two patients. Short stature and skeletal anomalies were also present. Molecular testing identified heterozygous pathogenic or likely pathogenic ANKRD11 variants: NM_013275.6:c.4087C > T (p.Arg1363Ter), NM_013275.6:c.3382_3383del (p.Asp1128GlufsTer41), and NM_013275.6:c.1977C > G (p.Tyr659Ter). All variants were predicted to result in premature termination. Renal fusion and complex vertebral anomalies were observed, suggesting possible underrecognized systemic involvement, although cautious interpretation is required given the small sample size. Conclusion This Saudi case series adds to the growing evidence of clinical heterogeneity in KBGS. Early recognition, molecular confirmation, multidisciplinary care, and longitudinal follow-up are essential to improve diagnosis, surveillance, and management.
Mai S. Labani, Z. Rahbeeni· Frontiers in Pediatrics· 0 citations
Pathogenic variants in KIF11 are linked to autosomal dominant syndromes with microcephaly, chorioretinopathy, lymphedema, and intellectual disability (MCLID), though adult presentations remain underreported. We report a 42-year-old female presenting with a de novo single-amino acid in-frame deletion in the KIF11 gene (c.1294_1296del; p.Glu432del), who exhibited severe intellectual disability, microcephaly, hypotonia, seizures, and self-injurious behavior. There was evidence of developmental delays, ophthalmologic findings, and impairments in speech and adaptive functioning in her clinical history. Trio whole exome sequencing identified a diagnostic pathogenic variant in KIF11 and a maternally inherited SCN3A variant of uncertain significance. The presentation of the case offers an unusual longitudinal perspective of over four decades, illustrating the variable expressivity and long-term outcome of KIF11 disorders. This report calls for the consideration of KIF11 variants in the differential diagnosis of syndromic developmental delay and microcephaly in adults and underlines the diagnostic as well as the prognostic importance of detailed genetic and phenotypic analysis, particularly in cases with de novo variants.
Thrishna Chathurvedula, Juvy L. Rabelas, Kareem Touleimat et al.· American Journal of Medical...· 0 citations
This case underscores that the genetic and neuropsychological identification of a neurodevelopmental disorder, together with the integration of tailored psychomotor interventions and contextual adaptations, can improve psychiatric management and daily functioning, and mitigate behavioral decline in adulthood, even following a prolonged diagnostic delay.
A. Bos-Roubos, Rosalie Te Brinke, A. Kattentidt-Mouravieva et al.· Frontiers in Psychiatry· 0 citations
This study expands the mutational landscape of JS in the Iranian population and underscores the utility of WES as a first-tier diagnostic tool for JS and related ciliopathies.
Sheyda Khalilian, Mohadeseh Fathi, Zahra Farbood et al.· Molecular Genetics and Metab...· 0 citations
Background: Kabuki syndrome is a rare multisystem neurodevelopmental disorder usually caused by pathogenic KMT2D or KDM6A variants, although a substantial minority of clinically typical patients remain molecularly unresolved. Autism spectrum disorder (ASD) has been reported in this population, but its prevalence and relationship to genotype remain poorly characterized. Case Presentation: We report a 12-year-old Moroccan boy, born to consanguineous parents, referred for severe behavioral disturbances including psychomotor hyperactivity, self-injurious behavior, and marked language delay. Physical examination showed characteristic craniofacial dysmorphism, long palpebral fissures with eversion of the lateral lower eyelids, blue sclerae, broad arched eyebrows, a depressed nasal tip, and a high-arched palate, together with microcephaly, postnatal growth restriction, infantile hypotonia, a waddling gait, and possible scoliosis, fulfilling international consensus criteria on dysmorphology, growth restriction, hypotonia, and musculoskeletal abnormalities for a clinical diagnosis of Kabuki syndrome. He also presented with severe ASD, attention-deficit/hyperactivity disorder, intellectual developmental disorder, and generalized epilepsy, established according to DSM5 criteria. Whole-exome sequencing identified no pathogenic variant in KMT2D or KDM6A, but revealed a heterozygous variant of uncertain significance in YWHAG (NM_012479.3:c.340G>A; p.Glu114Lys), a gene associated with developmental and epileptic encephalopathy. Pharmacological management included extended-release methylphenidate, which was discontinued because of paradoxical worsening of hyperactivity, followed by low-dose aripiprazole, which improved self-injurious behavior and agitation but caused a persistent tremor. Conclusions: This case shows that a well-characterized clinical gestalt remains sufficient to diagnose Kabuki syndrome despite negative first-line genetic testing, and that residual possibilities
M. Nokrou, S. Bounouh, Z. Maataoui et al.· Scholars Journal of Medical...· 0 citations
A retrospective multicenter case series of seven previously unreported individuals with heterozygous FBXW7 variants identified through clinical genetic testing expands the phenotypic spectrum associated with FBXW7-related neurodevelopmental disorder and highlights variable expressivity and incomplete penetrance.
Salvatore Savasta, F. Comisi, G. Dell’Isola et al.· Journal of Neurodevelopmenta...· 0 citations
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