The findings suggest that PPP1R12A-related disorders may exhibit a broader phenotypic variability than previously recognized and it is proposed that HL and inner ear malformations may represent novel features associated with this clinical spectrum.
Abstract
Background: Pathogenic variants in the PPP1R12A gene have been associated with a malformation syndrome involving the brain and the genitourinary systems (GUBS, MIM #618820). To date, neither hearing loss (HL) nor inner ear malformations have been reported in affected individuals, and these features are therefore not currently regarded as part of the PPP1R12A-related phenotype. Moreover, functional evidence supporting the pathogenicity of several reported variants remains limited. Methods: We investigated a 12.5-year-old patient presenting with profound bilateral sensorineural hearing loss associated with inner ear malformations, genitourinary and central nervous system abnormalities. The patient underwent comprehensive clinical, audiological and radiological assessments, followed by genetic testing via trio-based whole-exome sequencing (WES). The molecular consequences of the identified variant were evaluated through minigene splicing assay and RT–PCR analysis on RNA extracted from peripheral blood cells. Results: WES identified a novel heterozygous splicing variant (c.792+3A>C) in the PPP1R12A gene (NM_002480.3). Functional studies demonstrated that this variant causes complete skipping of exon 5, resulting in a frameshift and the introduction of a premature termination codon. RT–PCR analysis confirmed the presence of the alternatively spliced transcript lacking exon 5. In addition, an extensive review of the literature indicated that no clear genotype–phenotype correlation has yet been established for PPP1R12A-related disorders and, whereas the majority of previously reported patients share brain and genitourinary malformations our patient additionally presented with profound bilateral sensorineural HL and inner ear malformations. Conclusions: Our findings suggest that PPP1R12A-related disorders may exhibit a broader phenotypic variability than previously recognized and we further propose that HL and inner ear malformations may represent novel features associated with this clinical spectrum. Moreover, our study underscores the importance of functional studies for accurately defining the molecular consequences of novel variants and establishing appropriate clinical correlations.
BACKGROUND
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder. The clinical manifestations are pleiotropic, predominantly affecting the cardiovascular system (atrioventricular valve prolapse and regurgitation and aortic complications), the skeletal system (disproportionate elongation of long bones), and the ocular system (ectopia lentis and myopia). Pathogenic variants in the fibrillin-1 gene (FBN1) are the primary genetic cause of MFS.
METHODS
This study enrolled three Han-Chinese patients from three unrelated families, all of whom underwent comprehensive clinical assessments. Whole exome sequencing was used to screen for candidate variants, which were subsequently confirmed by Sanger sequencing. Further variant analyses, including bioinformatics-based prediction of variant pathogenicity, were then performed. For the potential splicing variant, a minigene construct was designed to evaluate its in vitro splicing effect.
RESULTS
Three heterozygous FBN1 variants were respectively identified in three probands, comprising a novel deletion (c.239_247 + 6del), a previously reported nonsense variant (c.4615C > T, p.(Arg1539*)), and a novel missense variant (c.6821G > A, p.(Cys2274Tyr)). Both in silico predictions and the in vitro minigene assay demonstrated the deletion of the terminal 11 nucleotides of exon 3 caused by c.239_247 + 6del variant, which is expected to cause a truncated protein, p.(Gln79Hisfs*46).
CONCLUSIONS
In this study, pathogenic FBN1 variants were identified in three patients, thereby confirming the clinical diagnosis of MFS. These findings facilitate diagnostic confirmation and genetic counseling for the affected families, contribute two novel variants to the FBN1 variant repository, and provide a comparative assessment of genotype-phenotype correlations.
Xing Zhao, L. Yuan, Yan Sun et al.· Clinica chimica acta; intern...· 0 citations
Aminoacylase 1 (ACY1) deficiency is a rare autosomal recessive inborn error of metabolism traditionally associated with neurological manifestations and characteristic urinary N-acetyl amino acid excretion. The association between ACY1 variants and congenital hearing loss has remained incompletely characterized, with sensorineural hearing impairment documented in a minority of reported cases. This systematic review synthesizes evidence from 2000 to 2026 on splice variants in ACY1 and their relationship to congenital hearing loss, with particular focus on the recently characterized c.1063-1G>A splice-site variant and its downstream pathogenic mechanisms. We examine clinical, biochemical, and functional evidence from patient studies, in vitro splicing assays, and zebrafish models that collectively support ACY1 as a candidate gene for hereditary hearing impairment. Transcriptomic profiling reveals that ACY1 deficiency disrupts critical inner ear developmental genes, including gfi1ab and atoh1a/b, through mechanisms potentially involving aberrant BMP signalling pathway regulation. This review consolidates current knowledge, identifies knowledge gaps, and proposes a framework for understanding the molecular pathology of ACY1-related hearing loss. Clinical Presentation: The proband presented with bilateral sensorineural hearing loss of congenital onset. Notably, developmental milestones were normal over a 4-year follow-up period, distinguishing this case from many previously reported ACY1D patients who exhibited neurological symptoms including intellectual disability and motor delay. This observation suggests that hearing loss may occur as an isolated manifestation of ACY1 dysfunction, without the broader neurological phenotype typically associated with the condition.
Erhan Oktay· International Journal of Adv...· 0 citations
Pathogenic variation of SLC26A4 gene causes both Pendred syndrome (PDS) and non-syndromic enlarged vestibular aqueduct (NSEVA/DFNB4), two autosomal recessive disorders. The former accounts for approximately 6% of human genetic hearing loss, making it the second most common form of syndromic deafness after Usher syndrome, while the latter is the most common radiological malformation associated with childhood sensorineural hearing loss (SNHL). Here, we used short- and long-read single-cell RNA sequencing (scRNA-seq) of pendrin-expressing cells in the murine cochlea to identify a novel short isoform of Slc26a4. We demonstrate that the short Slc26a4 isoform is expressed in both the inner ear and kidney and investigate its interactions and functions. We also characterize the genotype-phenotype association for SLC26A4-related hearing loss in the context of these two isoforms. These results provide a new reference for molecular profiling of pendrin and offer novel insights into cell-type-specific splicing events and SLC26A4-related hearing loss.
J. Koh, C. Affortit, K. Homma et al.· Human Genetics· 0 citations
Objective: To study the Progressive myoclonic epilepsies (PME) that is genetic disorders resulting from mutations in different genes, all characterized by the early onset of myoclonic seizures, and cognitive decline. The Potassium Channel Tetramerization Domain Containing seven (KCTD7) gene encodes for the BRC (broad complex), ttk (tramtrack), and bab/pox virus, and zinc finger domain, containing KCTD7 protein.
Methodology: The study was done in the Center of Excellence in Genomic Medicine and Research (CEGMR). The affected patient, a three-year-old Saudi female born to consanguineous parents, she underwent laboratory tests, EEG assessments, and Whole-Exome Sequencing (WES).
Results: Our results showed a novel five base pair deletion that was detected in homozygous state in the KCTD7 gene. Both the unaffected parents showed heterozygous mutation of the KCTD7 gene. Segregation analysis via Sanger sequencing supported the existence of the homozygous splice donor variant in NM_153033.4:c.493+2_493+6delTGA of KCTD7 gene in the patient.
Conclusion: The mutation is not reported in the literature yet; the particular phenotype that was observed in our patient is comparable to the ones that are described in the KCTD7 related pathologies, combined with segregation analysis indicating both parents carried the variant heterogeneously present is a strong indication that the identified mutation consists of probably pathogenic mutation. This finding will further increase our insight of the genetic basis of PMEs and role of KCTD7 gene mutations in Saudi population.
S. Alharazy, Peter Natesan Pushparaj, Rose Jelani et al.· Pakistan Journal of Medical...· 0 citations
The findings support the pathogenicity of this variant and further expand the pathogenic variant spectrum of the PPP2CA gene, and the observed genotype–phenotype correlation provides valuable information for prognosis and genetic counseling.
Lei Xu, Yanfeng Shen, Guixiang Zhang· Frontiers in Psychiatry· 0 citations
Heterozygous pathogenic variants in the
KCNQ2
gene underlie a broad phenotypic spectrum ranging from self-limited (familial) neonatal epilepsy (SeLNE) to developmental and epileptic encephalopathy or isolated intellectual disability. The
KCNQ2
gene encodes subunits of a voltage-gated potassium channel involved in neuronal excitability, and its mutations are known to have both loss-of-function (LoF) and gain-of-function (GoF) effects, resulting in distinct neurological syndromes. The recurrent missense LoF variant
KCNQ2
p.(Arg214Trp) has been previously reported in a single family with a presumed SeLNE phenotype, without detailed adult follow-up and with additional database-reported evidence suggesting a broader phenotype associated with this recurrent variant.
Here, we report a family with two adult carriers of the heterozygous
KCNQ2
p.(Arg214Trp) variant identified through whole-exome sequencing, including long-term follow-up into late adulthood. In addition, a literature review of previously reported cases carrying the same recurrent variant was performed.
Both individuals presented with early-onset focal epilepsy with a relapsing course, characterized by prolonged seizure-free periods followed by recurrence in adulthood. The proband demonstrated transient motor regression, developmental delay, moderate intellectual disability, ataxia and fine motor impairment. The father exhibited milder cognitive impairment and additional comorbidities in later life.
These findings challenge the concept of
KCNQ2
p.(Arg214Trp) as a self-limited epilepsy-associated variant and indicate a broader phenotypic spectrum, with persistence of epilepsy and associated neurological and non-neurological comorbidities into adulthood. Our report provides new insights into adult outcomes, aiding in genetic counseling and the long-term management of affected individuals. More extensive studies with larger cohorts carrying this variant are necessary to better define the full phenotypic spectrum and to distinguish comorbidities associated with different etiological factors, including perinatal factors.
P. Christova, M. Ostrožovičová, J. Neupauerová et al.· BMC Neurology· 0 citations