Aug 2026· American Journal of Medical Genetics. Part A· 0 citations· 20 references
Medicine
TL;DR
Call 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.
Abstract
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.
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.
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
Background 22q11.2 deletion syndrome (22q11.2DS) may be overlooked in adults when neurological care is prompted by pyramidal, gait, or parkinsonism-mimicking presentations rather than by congenital, developmental, psychiatric, or systemic features. Methods We retrospectively reviewed the clinical, imaging, and genetic findings of two unrelated adults whose neurological presentations led to whole-exome sequencing-based copy-number variant (CNV) detection of 22q11.21 deletions. Orthogonal confirmation by chromosomal microarray, multiplex ligation-dependent probe amplification (MLPA), quantitative polymerase chain reaction (qPCR), fluorescence in situ hybridization (FISH), or copy-number variation sequencing (CNV-seq) was not available; therefore, the reported deletion sizes and coordinates represent WES-derived estimates. Results Patient 1 presented with progressive lower-limb weakness, a spastic unsteady gait, pyramidal signs, dysarthria, and ataxic features, together with learning difficulty, palatal abnormalities, and a maternal history of similar gait disturbance and suspected epilepsy; analysis identified a 2.67-Mb deletion at 22q11.21. Patient 2 presented with progressive limb weakness, dysarthria, parkinsonism-mimicking rigidity and slowness, bilateral basal ganglia calcification, abnormal globus pallidus MRI signals, developmental delay, psychiatric symptoms, craniofacial features, and a maternal history of similar motor and cognitive impairment; analysis identified a 2.52-Mb deletion at 22q11.21. Conclusion These cases highlight diagnostic pitfalls and syndromic clues rather than establish a new mechanism. In adult neurology practice, developmental history, palatal or craniofacial abnormalities, basal ganglia calcification, psychiatric symptoms, and family history should prompt consideration of 22q11.2DS and genetic testing that is sensitive to copy-number variants.
Da-Ren Wu, Yue-Miao Wang, Dan-Dan Sun et al.· Frontiers in Neurology· 0 citations
This case highlights the wide phenotypic spectrum of CX43-related disorders and suggests the importance of testing the GJA1 gene in individuals with atypical presentations, including predominant or isolated neurological phenotypes such as late-onset spastic paraplegia.
Irene Ambrosetti, F. Palombo, Diego D'Angeli et al.· International Journal of Mol...· 0 citations
Multiple mitochondrial dysfunctions syndrome 6 (MMDS6), caused by biallelic likely pathogenic variants in PMPCB, is an extremely rare autosomal recessive childhood-onset neurodegenerative disorder, with only six reported cases to date, most resulting in early mortality. Pathogenic variants in VCP cause multisystem proteinopathy 1 (MSP1), an autosomal dominant adult-onset disorder encompassing inclusion body myopathy (IBM), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), typically presenting in mid-adulthood. We describe a 23-year-old female with two likely pathogenic variants presumed to be in trans in PMPCB and a co-occurring pathogenic VCP variant. She was misdiagnosed for over 20 years with early-onset VCP-related neurodegeneration due to a maternal family history of ALS. Her disease began at birth with microcephaly and progressed throughout childhood, including developmental regression, cerebellar and cerebral atrophy, optic atrophy, seizures, spasticity, dysarthria, and loss of ambulation. Initial genetic testing identified only the familial VCP variant. Updated genomic sequencing at age 23 revealed two likely pathogenic PMPCB variants, strong supporting a diagnosis of MMDS6. Her clinical features closely align with previously reported MMDS6 cases and are inconsistent with the typical adult-onset phenotype of VCP-associated disorders. While she shares overlapping features with VCP-related disease (limb-girdle weakness, spasticity, FTD), the timing and severity of her neurodevelopmental findings support MMDS6 as the primary diagnosis. Early mitochondrial dysfunction may predispose her to an accelerated or more severe future VCP-associated phenotype. This is the first report of combined likely pathogenic and pathogenic variants in PMPCB and VCP respectively, expanding the phenotypic spectrum of both disorders. The case underscores the necessity of periodic re-evaluation with advanced genetic testing, highlights important ethical and familial implications, and informs future diagnosis and management of patients with overlapping rare genetic conditions.
Reme Unuakhalu, Alexandra Purcell, Ishaan Jindal et al.· Molecular Genetics and Metab...· 0 citations
Background The presence of multiple rare Mendelian disorders in a single patient may mask clinical recognition when phenotypes overlap. We describe a patient with longstanding myotonia congenita due to a CLCN1 variant in whom an incidental discovery of severe hypocalcemia led to the diagnosis of GNAS-related pseudohypoparathyroidism (PHP). Exome reanalysis also identified an incidental homozygous pathogenic CYP1B1 variant associated with autosomal recessive glaucoma. Case presentation A 23-year-old man born to consanguineous parents was referred for management of chronic myotonia congenita, manifested by delayed motor milestones, frequent falls, contractures, and muscle hypertrophy. Electrophysiological assessment demonstrated myotonic discharges, and whole-exome sequencing (WES) identified a homozygous CLCN1 splice-site variant (NM_000083.3:c.1167-10T>C) known to cause myotonia congenita. During subsequent evaluation, he was found to have severe hypocalcemia, hyperphosphatemia, markedly elevated parathyroid hormone, basal ganglia and dentate calcifications, brachydactyly, subcutaneous calcifications, and mild hypothyroidism, raising suspicion for PHP. Genetic and ophthalmologic findings Reanalysis of WES data demonstrated a heterozygous frameshift GNAS variant (NM_080425.4:c.2494_2497delCTGA) and a homozygous CYP1B1 variant (NM_000104.4:c.182G>A; p.Gly61Glu) in addition to the CLCN1 defect. Sanger sequencing confirmed all three variants. The CYP1B1 finding prompted glaucoma-specialist evaluation. Visual acuity was 20/22 in the right eye and 20/25 in the left eye; intraocular pressures were 8 and 12 mmHg, respectively. The corneas were clear, cup-to-disc ratios were 0.4 and 0.5, and average retinal nerve fiber layer thicknesses were 74 and 75 µm. No definite glaucomatous damage was identified, and the patient was classified as a glaucoma suspect. After treatment with calcium, calcitriol, and ergocalciferol, serum calcium improved, parathyroid hormone levels declined, creatine kinase normalized, and the patient reported improved muscle stiffness and function. Conclusion This case demonstrates two clinically expressed Mendelian disorders together with a third actionable molecular finding. It highlights the importance of careful phenotyping, molecular testing, and cautious genotype-phenotype interpretation, particularly in consanguineous populations.
Noha N Mukhtar, Deema Alturki, Allianah D. Benito et al.· Frontiers in Endocrinology· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
