Pontocerebellar hypoplasia type 10 (PCH10) is an ultra-rare autosomal recessive neurodevelopmental disorder caused by biallelic pathogenic variants in CLP1, characterized by progressive microcephaly, global developmental delay, and hypotonia. Cystic fibrosis (CF) is an autosomal recessive disorder caused by pathogenic or likely pathogenic CFTR variants and primarily affects the respiratory and gastrointestinal systems. Although both conditions are individually well characterized, their coexistence in a single patient has not previously been reported. We describe a 2.5-year-old boy, born to consanguineous parents, who presented with severe microcephaly and global developmental delay, together with recurrent respiratory infections and growth retardation. Exome sequencing identified a homozygous CLP1 variant (NM_006831.3:c.419G>A, p.Arg140His), the same variant previously detected in a deceased sibling, confirming PCH10. A homozygous CFTR variant (NM_000492.4:c.1210-11T>G), corresponding to the 5T allele, was also detected and was classified as likely pathogenic according to ACMG/AMP criteria. The adjacent TG repeat length was not determined. The diagnosis of cystic fibrosis was subsequently supported by a positive sweat chloride test. This is, to our knowledge, the first reported dual molecular diagnosis of PCH10 and cystic fibrosis in the same individual. The case emphasizes the clinical value of comprehensive genomic testing for identifying a clinically independent, actionable coexisting Mendelian disorder in a child whose phenotype is not fully explained by a single diagnosis.
SHFM1 is caused by chromosomal rearrangements at the 7q21.3 locus affecting DLX5/6 function and its regulatory landscape. While hearing loss affects approximately 35-40% of SHFM1 patients, structural cochlear nerve pathology and growth impairment associated with large 7q21 deletions remain poorly characterized. We report a 7-year-old male presenting with severe proportionate short stature, global neurodevelopmental delay, and bilateral ectrodactyly referred for genetic evaluation. Physical examination revealed height SDS −4.05, head circumference SDS −4.88, and bilateral four-digit hands and three-digit feet accompanied by complex syndactyly. Temporal bone MRI demonstrated bilateral widening of the internal auditory canals. Cranial nerves VII and VIII could not be confidently followed beyond the canal entrance, with apparent fusion of the vestibulocochlear nerve complex resulting in a single nerve bundle appearance and imaging findings highly suggestive of bilateral cochlear nerve hypoplasia. Brain MRI revealed corpus callosum hypoplasia and prominent cortical volume loss. Endocrine evaluation, including thyroid function, celiac serology, and IGF-1, was unremarkable, with growth velocity appropriate for age and prepubertal status despite severe baseline short stature, supporting a genetic rather than endocrine etiology. Chromosomal microarray analysis demonstrated a de novo 9.1 Mb heterozygous deletion at arr[GRCh38] 7q21.13q22.1(89,457,324_98,525,793)×1, encompassing DLX5, DLX6, and known regulatory elements within the DLX5/6 locus. The deletion overlaps all three phenotypic subregions previously proposed within the SHFM1 locus, providing a molecular basis for the simultaneous occurrence of ectrodactyly, hearing loss, and craniofacial dysmorphism. Bilateral cochlear nerve hypoplasia, to our knowledge, has only rarely been reported in association with 7q21 deletions and carries distinct implications for cochlear implantation outcomes. This case expands the phenotypic spectrum of large 7q21 deletions and suggests that larger deletions may contribute to broader phenotypic involvement.
Introduction: Epilepsy is a common neurological disorder characterized by recurrent seizures, in which genetic factors play a key role. Among epilepsy-associated genes, CHRNA2, CHRNA4, and CHRNB2 encode subunits of neuronal nicotinic acetylcholine receptors (nAChRs), which are essential for regulating neuronal excitability and synaptic transmission. However, many missense variants in these genes are classified as variants of uncertain significance (VUS), limiting their clinical interpretation. Methods: We evaluated missense VUS in CHRNA2, CHRNA4, and CHRNB2 using a gene-set-calibrated, mechanism-aware in silico framework. LoGoFunc assigned each candidate to a gain- or loss-of-function branch. We ranked both branches using a REVEL–AlphaMissense–CADD consensus layer, MutScore, and PrimateAI; we also used ConSurf, DynaMut2, and population rarity for the loss-of-function branch. We assessed performance against a curated benchmark set of 41 pathogenic or likely pathogenic and 136 benign or likely benign missense variants. Results: The framework identified 381 candidate variants, including 259 in the gain-of-function branch, 115 in the loss-of-function branch, with seven unassigned. Of these, 94 gain-of-function and 38 loss-of-function candidates met the highest-priority criteria. During candidate retrieval, we recovered 35 of 41 pathogenic reference variants. The fully supported tier achieved 97.8% specificity, 88.5% positive predictive value, and a Matthews correlation coefficient of 0.642. Conclusion: This mechanism-aware framework reduces a broad range of uncertain variants to a prioritized list of testable candidates, each with a distinct functional hypothesis for laboratory validation.
Introduction: White-Sutton syndrome (WS; OMIM #616364) is a rare autosomal-dominant neurodevelopmental disorder caused by heterozygous loss-of-function variants in POGZ. Although intellectual disability and dysmorphism are well recognised, obesity has emerged as a recurrent yet undercharacterised endocrine-metabolic feature. Case Presentation: We report an 11-year-old boy who presented with a BMI of 28.8 kg/m² (BMI-SDS +2.68) without any history of neonatal hypotonia, feeding difficulty or hyperphagia. Biochemistry showed marked insulin resistance (fasting insulin 32 mIU/mL) and prediabetes (HbA1c 6.0%). Targeted testing for PWS and other recurrent CNV syndromes was negative. Exome sequencing revealed a de novo, likely-pathogenic frameshift variant POGZ c.2987dup p.(Arg997Profs*30), establishing the diagnosis of WS. A review of the published literature showed that elevated BMI or overt obesity is reported in approximately 20–40% of cohorts and characteristically develops without hyperphagia. Conclusion: WS should be considered in the differential diagnosis of children with early-onset obesity and developmental delay, particularly when classical features of PWS are absent. The case supports an appetite-independent, chromatin-mediated mechanism of metabolic dysregulation in POGZ-related disorder. Routine metabolic follow-up, sleep evaluation and a multidisciplinary management plan are warranted in all affected individuals.
Introduction: Myotonic dystrophy type 1 (DM1) is caused by an unstable CTG trinucleotide repeat expansion in the Dystrophia Myotonica Protein Kinase (DMPK) gene, and Southern blot analysis has traditionally served as the gold-standard method for sizing large expansions. However, Southern blotting is technically demanding and can produce false-negative or indeterminate results in cases affected by somatic mosaicism, partial DNA degradation, or low expanded-allele representation, posing a diagnostic challenge especially in mildly symptomatic or elderly patients. Long-read sequencing (LRS) has emerged as a promising alternative capable of directly sequencing native DNA molecules across the entire repeat tract, but reports applying LRS to resolve Southern blot-negative cases with a clinically compatible phenotype remain scarce. Case Presentation: A 67-year-old man presented with acute hypercapnic respiratory failure and dysphagia. He had a history of longstanding, non-progressive dysarthria and chronic difficulty relaxing his fingers. Neurological examination showed distal limb weakness, grip and percussion myotonia, and a myopathic face with characteristic facial and temporal muscle wasting. Needle electromyography demonstrated myopathic changes with profuse myotonic discharges, raising strong clinical suspicion of myotonic dystrophy. However, Southern blot analysis of long-range PCR products for the DMPK CTG repeat expansion returned a negative result, discordant with the clinical phenotype. Given the high pretest probability of DM1, targeted long-read sequencing of the DMPK locus was performed using the PacBio PureTarget repeat expansion panel on a PacBio Revio system, an amplification-free, CRISPR/Cas9-based enrichment platform. This analysis identified a pathogenic expanded allele of approximately 297 CTG repeats (a consensus estimate from 945 spanning high-fidelity reads), establishing the molecular diagnosis of DM1 and resolving the discrepancy caused by the false-negative Southern blot result. Conclusion: This case illustrates that amplification-free, CRISPR/Cas9-targeted high-fidelity long-read sequencing can detect and size pathogenic DMPK CTG repeat expansions that are not detected by conventional Southern blot analysis, supporting its use as a complementary or confirmatory diagnostic tool in diagnostically challenging cases of DM1.
