Biomedical subjects

Amelle Shillington

Publications and source records attributed to Amelle Shillington.

5 recordsLinked to original sources

PubMed2026

Moebius-Plus Phenotype With Positive RCEM Episignature May Indicate Broader Embryologic Malformation Spectrum Detectable by Methylation Profiling.

Moebius syndrome (OMIM #157900) is a rare congenital cranial dysinnervation disorder characterized by abducens (CN VI) and facial (CN VII) nerve palsies with variable craniofacial and limb anomalies. Despite advances in genomic testing, the majority of patients remain genetically unexplained. Episignature testing, which detects syndrome-specific DNA methylation patterns, has emerged as a complementary diagnostic tool for conditions with shared developmental mechanisms. We describe an 8-month-old male born prematurely with bilateral clubfoot, craniofacial dysmorphism, feeding difficulty requiring gastrostomy tube placement, and respiratory failure requiring tracheostomy. Neuroimaging demonstrated absence of bilateral abducens and facial nerves with pontocerebellar hypoplasia, supporting a clinical diagnosis of Moebius syndrome. Extensive genetic evaluation, including genome sequencing and targeted testing for hypotonia and hypoventilation syndromes, was nondiagnostic. Episignature analysis revealed a moderately positive methylation signature consistent with a recurrent constellation of embryonic malformation (RCEM), concordant with two of three previously validated RCEM classifier models. To our knowledge, this is the first report of a patient with a positive RCEM episignature and Moebius syndrome, suggesting a common embryologic pathway. Episignature testing may represent a valuable diagnostic tool in patients with Moebius syndrome and related craniofacial-limb malformation spectra when conventional genomic testing is unrevealing.

RCEM↗

PubMed2026

The long road to diagnosis: recessive PMPCB deficiency hidden behind a dominant familial VCP defect.

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.

Dual molecular diagnosis↗

PubMed2026

Abnormal ClC-3/TMEM9-mediated endosomal ion transport in CLCN3-associated neurodevelopmental disease.

Endolysosomal abnormalities are particularly detrimental to the nervous system and have been implicated in neuropsychiatric disorders. Key regulators of the lysosomal and endosomal luminal ion homeostasis are CLC chloride/proton exchangers. We report 15 individuals carrying variants in CLCN3, encoding a ubiquitous endosomal 2Cl-/H+ exchanger, and provide updated clinical information for 5 previously reported individuals. Subjects displayed a broad spectrum of neuropsychiatric symptoms, including developmental delay, intellectual disability, and epilepsy. To reveal the pathogenic mechanism, we investigated ClC-3 variants-mediated ion transport and its regulation by the recently discovered inhibitory beta subunit TMEM9. 12/20 missense variants exhibited altered properties and fell into two classes: those affecting the region binding inhibitory TMEM9 carboxy-termini, and those that broaden the voltage range over which ClC-3 conducts ions. Surprisingly, the latter variants also attenuated TMEM9-mediated inhibition. Both classes produced a toxic gain-of-function, as evident from endolysosomal vacuolization by mutant ClC-3/TMEM9 overexpression. Our results expand the genetic and clinical spectrum of CLCN3-related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9.

Chloride Channels↗

PubMed2026

Characterization of the genotypic and phenotypic spectrum of TCF7L2-related neurodevelopmental disorder (TRND).

PURPOSE: TCF7L2 (OMIM 602228; HGNC:11641) is a transcription factor and a critical effector of the Wnt/ β-Catenin pathway. In 2021, 11 pediatric patients with monoallelic predicted loss-of-function (pLOF) TCF7L2 variants and syndromic features were observed. Characterization of patients with pLOF TCF7L2 variants and neurodevelopmental features-herein referred to as TCF7L2-related neurodevelopmental disorder-is urgently needed. METHODS: We leveraged multiple methods (eg, GeneMatcher, DECIPHER, literature review, and public/private repositories) to identify an international cohort of 76 patients with pLOF TCF7L2 variants and neurodevelopmental features and phenotypically characterized them. We also retrospectively searched for an independent cohort of adults with pLOF TCF7L2 variants (n = 11) from more than 60,000 PennMedicine BioBank patients. RESULTS: Among 76 patients with pLOF TCF7L2 variants, speech delay (95.3%), craniofacial dysmorphisms (73.3%), ophthalmologic conditions (65.5%), autism (62.1%), and orthopedic abnormalities (52.6%) were the most commonly observed. Phenotypic differences did not cluster by variant type or genomic locus. Among PennMedicine BioBank patients, an association of nominal significance with type 2 diabetes with renal manifestations (odds ratio = 5.8; P = .03) was detected, warranting further investigation. CONCLUSION: This study represents the most comprehensive characterization of TCF7L2-related neurodevelopmental disorder to date, a novel neurodevelopmental disorder, defining its genotypic and phenotypic spectra. We opened a Simons Searchlight natural history study that is now available for patient enrollment to enhance the understanding of this condition.

Neurodevelopmental syndrome↗

PubMed2024

RORA-neurodevelopmental disorder: A unique triad of developmental disabilities, cerebellar anomalies, and myoclonic seizures.

PURPOSE: RORA encodes the RAR-related orphan receptor-α, playing a pivotal role in cerebellar maturation and function. Here, we report the largest series of individuals with RORA-related-neurodevelopmental disorder. METHODS: Forty individuals (30 unrelated; 10 siblings from 4 families) carrying RORA pathogenic/likely pathogenic variants were collected through an international collaboration. RESULTS: The 33 variants (29 de novo, 4 inherited, and 1 shared), identified by genome/exome sequencing (n = 21), chromosomal microarray analysis (n = 7), or gene panels (n = 4), included frameshift (n = 18/33), missense (n = 9/33), and stop codon (n = 6/33). Developmental disability (n = 32/37), intellectual disability (n = 22/32), and cerebellar signs (n = 25/34) were the most striking clinical features. Cerebellar symptoms were divided into early-onset, late-onset, and progressive subgroups. Cerebellar hypoplasia, atrophy, or both (n = 16/25) were more frequent in individuals with missense variants in the DNA-binding domain. Epilepsy (n = 18/38), with prominent myoclonic seizure types (n = 11/18), was classified in (1) genetic generalized epilepsy (n = 10/18) with a syndromic diagnosis identifiable for 6: epilepsy with eyelid myoclonia (n = 5/6) and epilepsy with myoclonic absence (n = 1/6); (2) developmental and epileptic encephalopathy (n = 5/18); and (3) unclassified (n = 3/18). A participant with rapid deterioration of visual acuity and cone/rod dystrophy was reported. CONCLUSION: Missense variants in DNA-binding domain correlate to a more severe cerebellar phenotype. The RORA-related-neurodevelopmental disorder triad comprises developmental disability, cerebellar features, and a spectrum of myoclonic epilepsy.

Humans↗