Otopalatodigital spectrum disorders (OPDSD), comprising otopalatodigital syndromes types 1 and 2 (OPD1, OPD2) and frontometaphyseal dysplasia (FMD), are rare X-linked disorders caused by FLNA gene variants, with phenotyp...Otopalatodigital spectrum disorders (OPDSD), comprising otopalatodigital syndromes types 1 and 2 (OPD1, OPD2) and frontometaphyseal dysplasia (FMD), are rare X-linked disorders caused by FLNA gene variants, with phenotypes ranging from mild skeletal anomalies to severe multisystem malformations. We describe two unrelated cases: a 14-year-old male (P1, FMD) and an aborted fetus (P2, OPD2). Whole-exome sequencing identified hemizygous maternally inherited FLNA gene variants in P1 (c.733G>A; p.Glu245Lys) and P2 (c.3707G>A; p.Gly1236Asp, novel), expanding the OPD2 mutational spectrum (NM_001110556). P1 presented with facial dysmorphism, dental anomalies, flattened thumbs, and dermatoglyphic changes; P2 showed facial dysmorphism, skeletal and cardiac malformations, and omphalocele. These cases underscore the breadth of OPDSD phenotypic variability and add novel genetic data. Dental management demands multidisciplinary care from infancy through adolescence, including cleft repair, orthodontics for micrognathia and facial aesthetics, and treatment of dental anomalies. Early recognition, molecular diagnosis, and coordinated management are critical for improving outcomes in these complex disorders.
Intellectual disability (ID) is a genetically heterogeneous disorder, and many causative genes remain unidentified. FSCN1 encodes an actin-bundling protein essential for neuronal development, but its role in human neurod...Intellectual disability (ID) is a genetically heterogeneous disorder, and many causative genes remain unidentified. FSCN1 encodes an actin-bundling protein essential for neuronal development, but its role in human neurodevelopmental disorders has not been clinically established. By revisiting data from a previously studied Iranian ID cohort, we identified two unrelated families carrying the same rare pathogenic missense variant in FSCN1 (c.665C>A; p.Ala222Asp). Affected individuals exhibited moderate to severe ID with consistent craniofacial features, including a prominent maxilla, long face, broad forehead, and thick lower lip. In silico tools predicted the variant as damaging and destabilizing, and the affected residue is highly conserved. This study provides the first clinical evidence linking FSCN1 to syndromic ID with craniofacial anomalies. The craniofacial features observed in our patients are consistent with experimental evidence from animal models. Together with supportive data from animal models, our findings suggest FSCN1 as a candidate gene for rare or ultra-rare forms of ID and warrant further functional studies to elucidate its precise pathogenic mechanisms.
MAP1B (microtubule-associated protein 1B) encodes a cytoskeletal regulator critical for neuronal migration, axon guidance, and cortical circuit formation. Disease-causing variants (DCVs) in MAP1B have recently emerged as...MAP1B (microtubule-associated protein 1B) encodes a cytoskeletal regulator critical for neuronal migration, axon guidance, and cortical circuit formation. Disease-causing variants (DCVs) in MAP1B have recently emerged as a cause of neurodevelopmental disorders characterized by intellectual disability, epilepsy, and cortical malformations, including periventricular nodular heterotopia (PVNH) and polymicrogyria (PMG). However, the phenotypic and neuroimaging spectrum associated with MAP1B-related disease remains incompletely defined. We describe seven affected individuals from three unrelated families with pathogenic MAP1B variants. Clinical, neuroimaging, and genetic data were analyzed in the context of emerging literature to delineate the pathogenic mechanisms and phenotypic variability associated with MAP1B dysfunction. All individuals carried loss of function MAP1B variants. Clinical features included global developmental delay, intellectual disability, behavioural dysregulation, and focal epilepsy. Neuroimaging revealed anteriorly predominant PVNH in four of five cases with neuroimaging available. These findings reinforce MAP1B's central role in cytoskeletal regulation, neuronal positioning, and synaptic connectivity. Functional data from animal and cell models support a mechanism involving impaired microtubule stabilization, altered growth cone dynamics, and dysregulated axon branching. Our case series expands the clinical and radiological phenotype associated with MAP1B-related disorders and highlights its position as a key cytoskeletal regulator in human corticogenesis. Systematic genotype-phenotype correlation and functional studies are needed to inform diagnostic interpretation and explore therapeutic avenues in MAP1B-associated disease.
Connector enhancer of kinase suppressor of Ras2 (CNKSR2) is critical in neuronal dendrite growth. Hemizygous pathogenic variants of CNKSR2, which is located at Xp22.12, are associated with intellectual disability, epilep...Connector enhancer of kinase suppressor of Ras2 (CNKSR2) is critical in neuronal dendrite growth. Hemizygous pathogenic variants of CNKSR2, which is located at Xp22.12, are associated with intellectual disability, epilepsy, and developmental and epileptic encephalopathy with spike wave activation during sleep. As an X-linked recessive genetic disorder, neurological symptoms usually manifest in males, while female carriers are typically asymptomatic. Here, we report a girl (Patient 1) and boy (Patient 2) with a pathogenic truncated variant of CNKSR2. Patient 1 had intractable epilepsy and severe developmental regression; her electroencephalogram showed continuous spike-and-wave activity during sleep. Whole-genome sequencing (WGS) revealed a heterozygous CNKSR2 c.2134C>T, p.(Arg712Ter) variant (de novo, previously reported), and X-chromosome inactivation analysis of her white blood cell DNA showed marked skewing (85:15). Her clinical symptoms were more severe than those of previously reported female patients, but they improved with ethosuximide and sulthiame treatment. Patient 2 had epilepsy and Angelman syndrome-like symptoms. WGS revealed a Clinical Genetics hemizygous c.492C>A, p (Cys164Ter) CNKSR2 variant (maternal or novel). The strength of the X-chromosome inactivation skewing may be related to severity. These novel pathogenic CNKSR2 variants have expanded the phenotypic spectrum of this disease.
TNS2-related Nephrotic Syndrome (TNS2-NS) is a rare form of nephrotic syndrome inherited in an autosomal recessive manner, caused by pathogenic variants in the TNS2 gene. Only five cases have been documented, all involvi...TNS2-related Nephrotic Syndrome (TNS2-NS) is a rare form of nephrotic syndrome inherited in an autosomal recessive manner, caused by pathogenic variants in the TNS2 gene. Only five cases have been documented, all involving biallelic missense variants with symptoms appearing in early childhood. We describe a 34-year-old man with nephrotic syndrome who was found to have a homozygous stop-gain mutation in TNS2 via exome sequencing. This is the first reported human case with a truncating TNS2 variant and adult-onset disease, differing from earlier cases with early onset and missense mutations. While studies in mice show that Tns2 is vital for kidney health, similar human data are lacking. Our results indicate that null mutations in TNS2 could also lead to nephrotic syndrome and may result in the disease manifesting later in life.
Dyskeratosis congenita (DC) is a rare genetic disorder caused by impaired telomere maintenance, leading to diverse clinical manifestations, including bone marrow failure, mucocutaneous abnormalities, and multi-organ dysf...Dyskeratosis congenita (DC) is a rare genetic disorder caused by impaired telomere maintenance, leading to diverse clinical manifestations, including bone marrow failure, mucocutaneous abnormalities, and multi-organ dysfunction. Here, we report a 14-year-old male patient presenting with microcephaly, developmental delay, synostoses, cerebellar hypoplasia with ataxia, and an immunodeficiency condition, but lacking classical DC features such as nail dystrophy and skin hyperpigmentation. WGS revealed two variants in the PARN gene: a known pathogenic missense variant (c.1045C > T, p.Arg349Trp) and a novel intronic variant (c.178-28T > C). Functional RNA analysis demonstrated that the intronic variant disrupts the branch point sequence, leading to exon 4 skipping and nonsense-mediated decay (NMD) of a significant proportion of transcripts. This study confirms the pathogenicity of the intronic variant and underscores the importance of functional validation in interpreting noncoding variants, particularly in genetically heterogeneous disorders like DC. Our findings expand the molecular and phenotypic spectrum of PARN-related DC and highlight the utility of WGS reanalysis and RNA studies in resolving diagnostically challenging cases.
Congenital limb anomalies remain without an etiological diagnosis in up to 65% of patients. To help close this gap, we describe the genetic diagnostic outcomes of a large cohort. Patients whose primary indication for gen...Congenital limb anomalies remain without an etiological diagnosis in up to 65% of patients. To help close this gap, we describe the genetic diagnostic outcomes of a large cohort. Patients whose primary indication for genetic consultation was a limb anomaly were included from 2014 to 2024. Demographic, investigation, and diagnostic information were extracted, described, and compared. One hundred and thirty-two patients were included in the final cohort, with an average molecular diagnostic yield of 36%. The most common conditions were polydactyly (24%) and radial anomalies (19%). Fifty percent had syndromic features. Seven (5%) patients underwent chromosomal microarray (CMA) only, 81 (63%) CMA and a gene panel, and 43 (32%) subsequently underwent exome sequencing. Exome yielded a diagnosis in 11 (25%). We identified 25 novel mutations in known disease-causing genes, including TBX3 (3 cases) and expanded the phenotype of several loci, including BMP4 and HNRNPH2. Finally, we identified two new limb anomalies candidate loci, for which previously published mouse studies from other groups suggested roles in limb development: HOXA11 and a 2q31.1 deletion involving HOXD10 and HOXD12. This represents the second largest described limb anomalies cohort. Exome-wide sequencing associated with literature and database searches for mouse data represents an opportunity to identify novel etiologies in this group of disorders, including two candidate loci we identified.
Ciliopathies are rare genetic disorders characterized by significant genetic and phenotypic variability. Over 140 proteins localized to primary cilia, which are sensory organelles essential for vertebrate development, ar...Ciliopathies are rare genetic disorders characterized by significant genetic and phenotypic variability. Over 140 proteins localized to primary cilia, which are sensory organelles essential for vertebrate development, are implicated. TMEM17 encodes a transmembrane protein at the ciliary transition zone and was previously proposed as a potential ciliopathy gene, based on reports of individuals from two families with orofaciodigital syndrome type 6 (OFD6) and Joubert syndrome (JS). Here, we report two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts, in whom exome sequencing identified a founder homozygous missense variant (Arg94Trp) in TMEM17, affecting a highly conserved residue. This expands the TMEM17-associated phenotypic spectrum to include Meckel syndrome (MKS). Comprehensive functional analyses of all known TMEM17 variants, using patient tissues/cells and a C. elegans model system, demonstrate a loss-of-function mechanism. Our study reveals severe functional consequences, including TMEM17 destabilization and mislocalization, anomalies in cilium composition and function, and abrogation of Sonic Hedgehog signaling. These experiments confirm the pathogenicity of all TMEM17 variants and underscore its essential role at the ciliary transition zone. Collectively, our findings establish TMEM17 as a bona fide ciliopathy gene, associated with a wide phenotypic spectrum ranging from viable syndromes (OFD6 and JS) to a fetal-lethal condition (MKS).
The BRCA2 c.156_157insAlu variant is a Portuguese founder mutation implicated in hereditary breast and ovarian cancer (HBOC). This study aims to determine its occurrence and clinical implications in the northern interior...The BRCA2 c.156_157insAlu variant is a Portuguese founder mutation implicated in hereditary breast and ovarian cancer (HBOC). This study aims to determine its occurrence and clinical implications in the northern interior region of Portugal. A retrospective study of 571 individuals referred for HBOC genetic counseling and testing between 2021 and 2024 was conducted. Genetic screening was performed using next-generation sequencing of 27 hereditary cancer genes, with confirmatory PCR for BRCA2 c.156_157insAlu. Pathogenic or likely pathogenic variants were detected in 19.8% of participants, with BRCA1/2 variants accounting for 5.4%. The BRCA2 c.156_157insAlu variant was identified in 6 individuals (25% of all BRCA2 pathogenic variants identified), including breast cancer patients and asymptomatic carriers. Clinically, it was associated with early onset and contralateral breast cancer. Cascade testing and genetic counseling were offered to at-risk relatives. The BRCA2 c.156_157insAlu variant remains a significant contributor to HBOC in northern Portugal. Its high local proportion among BRCA2 variants supports the implementation of targeted genetic testing strategies, enhancing early detection and personalized cancer risk management.
Primary mitochondrial myopathies (PMMs), a group of genetic mitochondrial oxidative phosphorylation disorders, primarily affect skeletal muscle function. No approved treatments for PMM exist, and patient information is l...Primary mitochondrial myopathies (PMMs), a group of genetic mitochondrial oxidative phosphorylation disorders, primarily affect skeletal muscle function. No approved treatments for PMM exist, and patient information is limited. The international RePOWER registry (NCT03048617) assessed genotypic and phenotypic relationships in PMM and identified patients for MMPOWER-3 (elamipretide Phase 3 study). RePOWER enrolled screened and ambulatory patients aged 16-80 years. With signs and/or symptoms of PMM (N = 376; 60.4% female; mean [SD] age 42.6 [14.4] years; ~75% with an mtDNA variant and ~25% with an nDNA variant). Baseline information, current symptoms, qualityoflife, and functional assessments (6-Minute Walk Test [6MWT], Triple-Timed Up-and-Go [3TUG] Test, and 5-Times Sit-to-Stand Test [5XSST]) were captured. Accredited laboratory and genetic testing methods were available to most patients. The majority of enrolled PMM patients presented with progressive external ophthalmoplegia and fatigue. US patients were observed to use more medical interventions. Compared to non-US patients, US patients did not perform as well on the 6MWT (mean 364.6 vs. 375.2 m) and 5XSST (mean 21.6 vs. 18.6 s); US patients performed better on the 3TUG test (mean 40.2 vs. 45.0 s). The RePOWER registry provided data on patients with genetically confirmed PMM, thereby improving our understanding of PMM diagnosis and treatment and the differences in global mitochondrial clinical practice.
Facioscapulo-humeral muscular dystrophy is characterized by a distinctive phenotype, although a wide range of clinical expressions is observed, possibly reflecting different disease progression rates or complex genetic m...Facioscapulo-humeral muscular dystrophy is characterized by a distinctive phenotype, although a wide range of clinical expressions is observed, possibly reflecting different disease progression rates or complex genetic mechanisms. To date, the diagnostic criteria for FSHD rely on identifying the genetic signature of the disease (reduced D4Z4 allele, permissive 4q allele, hypomethylation, and in some cases variants in modifier genes). However, interpreting genetic data requires careful correlation with the phenotype, especially in atypical cases. The study included a cohort of 42 patients with a D4Z4 contraction or belonging to a pedigree in which DRAs segregated but who were selected due to presenting atypical clinical features or an unexpected disease severity according to the Comprehensive Clinical Evaluation Form (CCEF). The 42 underwent 4q subtype analysis, DNA methylation assessment, whole-exome sequencing (WES) and segregation analysis. In 24 cases, WES identified likely pathogenic or pathogenic variants in genes associated with different neuromuscular disorders, in some cases possibly compatible with the observed phenotype. Methylation analysis proved useful in distinguishing asymptomatic and atypical cases, prompting differential diagnosis. Our results emphasize the importance of a detailed phenotypic characterization of patients with a suspicion of FSHD and, in the case of atypical phenotypes, the combination of D4Z4 sizing with other procedures such as WES.
Sarcoglycanopathies are autosomal recessive muscular dystrophies characterized by progressive muscle weakness and represent a major subset of limb-girdle muscular dystrophies (LGMDs). They result from pathogenic variants...Sarcoglycanopathies are autosomal recessive muscular dystrophies characterized by progressive muscle weakness and represent a major subset of limb-girdle muscular dystrophies (LGMDs). They result from pathogenic variants in sarcoglycan genes (SGCA, SGCB, SGCD, and SGCG), which encode subunits of a tetrameric transmembrane complex that stabilizes the dystrophin-associated glycoprotein complex. Among these, SGCG is commonly affected and is associated with LGMD2C/R5. Several founder variants in SGCG have been reported across different populations. Here, we describe a novel founder allele in the Turkish population, comprising a missense variant (c.392A>G, p.Lys131Arg) and a copy number gain (exon 1-4 duplication) that occurs in cis. Through an inductive screening strategy, we identified these linked variants in 11 individuals: five affected patients from four families and six unrelated incidental carriers. Haplotype analysis confirmed a shared genomic background supporting a founder effect. Affected individuals carried the allele in a homozygous or compound heterozygous state with other pathogenic SGCG variants. Molecular and histopathological investigations revealed that the duplicated allele results in mRNA decay and loss of SGCG protein expression. This study represents the first report of a disease-associated duplication in SGCG, highlighting a novel founder allele composed of two linked variants that contribute to sarcoglycanopathy in a specific population.
Following termination of pregnancy for fetal anomaly or unexplained perinatal death (PND), clinical geneticists advise on possible genetic causes and likelihood of recurrence, often with limited use of molecular analysis...Following termination of pregnancy for fetal anomaly or unexplained perinatal death (PND), clinical geneticists advise on possible genetic causes and likelihood of recurrence, often with limited use of molecular analysis. In the Australian Genomic Autopsy Study (GAS) cases that were unresolved following standard-of-care investigations underwent exome and/or genome sequencing (ES/GS). This diagnostic before-and-after study measured the changes in clinical management, in terms of the effect on clinical counselling that was provided to parents following ES/GS. Clinicians were surveyed before and after receiving sequencing results about the likelihood of recurrence and the reproductive planning advice they would provide to families. 161 pairs of before-and-after surveys were completed. Clinician estimates regarding PND recurrence changed for 45% (73/161) of families after receiving test results, despite a genetic diagnosis being found in only 19%. Families with an 'unknown likelihood' of recurrence reduced from 26% to 15% (p = 0.01). The information provided to parents about recurrence and reproductive planning increased significantly, both with and without a diagnosis, and clinicians reported that most parents expressed value was obtained from the investigation. The utility of genomic autopsy for clinical management is not restricted to families with a genetic finding.
The Mennonite population has a unique history of 500 years of genetic isolation shaped by at least three demographic bottlenecks, founder effects, inbreeding, epidemics, and migrations. To evaluate their susceptibility f...The Mennonite population has a unique history of 500 years of genetic isolation shaped by at least three demographic bottlenecks, founder effects, inbreeding, epidemics, and migrations. To evaluate their susceptibility for monogenic diseases (MD), we performed whole-exome sequencing on 325 volunteers from two South Brazilian Mennonite settlements (one urban and another rural). We identified 23 pathogenic variants (P) and 27 likely P, with 22.8% accounting for endocrine, nutritional, and metabolic MDs, 17.5% for developmental anomalies, and 10.5% for nervous system MDs. HFE rs1800562 causing hereditary hemochromatosis presented the highest frequency (7.54%), followed by BTD rs13078881 for biotinidase deficiency (7.08%), FLG rs61816761 for ichthyosis vulgaris and atopic dermatitis (3.38%), and FANCM rs147021911 for Fanconi anemia (3.08%). Genomic and genealogical analysis confirmed their European origin, with very low consanguinity and high heterozygosity coefficients, confirming a random selection of refugees that emigrated from widespread settlements in Russia to Brazil in 1930. There was also a slight deviation to Native Americans for self-reported admixed Mennonites. Even so, founder effects occurred for 96% of P, whose frequencies differed from non-Finnish Europeans, Amish, and Brazilian populations. These findings highlight the genetic risks in this population, reinforcing the importance of genetic counseling, screening programs, and Personalized and Preventive Medicine strategies to mitigate health risks associated with inherited conditions.
Avascular necrosis (AVN) and minimal trauma fractures (MTF) cause significant morbidity in patients with telomere biology disorders (TBDs). TBDs are associated with very high risks of bone marrow failure, pulmonary fibro...Avascular necrosis (AVN) and minimal trauma fractures (MTF) cause significant morbidity in patients with telomere biology disorders (TBDs). TBDs are associated with very high risks of bone marrow failure, pulmonary fibrosis, cancer, and many other complications due to pathogenic germline variants in genes essential for telomere function and maintenance. To understand the extent to which AVN and MTF occur in TBDs and identify areas requiring more research in the role of telomeres in bone biology. We assessed the occurrence of AVN and MTF in 233 patients with TBDs. An age, gender, and gene-matched TBD patient control group was used to assess associations between AVN/MTF and clinical characteristics. Forty-two (18%) patients with TBD developed at least one AVN and/or MTF event with 19 patients experiencing their first event in childhood. AVN and MTF were most common in patients with autosomal or X-linked recessive, or heterozygous TINF2 disease (19/36 AVN and 17/19 MTF). Androgen and corticosteroid use were more common in patients with AVN compared with matched patient controls (41.2% vs. 16.3%, p < 0.05 and 41.2% vs. 14%, p < 0.01, respectively); however, 57.1% of patients experienced AVN and/or MTF events in the absence of androgen or corticosteroid use. Severe bone marrow failure and hematopoietic cell transplantation history were significantly more common in MTF patients than in controls (44.2% and 30.2% respectively, p < 0.05). There were no statistically significant associations between low bone mineral density or vitamin D deficiency and AVN or MTF. AVN and MTFs are common, debilitating complications in TBDs and frequently occur independently of androgen or corticosteroid use. Our results underscore the need for disease-specific translational studies as well as improved prevention and therapeutic options for patients with TBDs. Trial Registration: ClinicalTrials.gov identifier: NCT00027274.
Cystic kidney diseases are genetically and clinically heterogeneous. Despite advances in genetic testing, some patients remain undiagnosed, limiting targeted care. This study explores the genetic causes in Lithuanian pat...Cystic kidney diseases are genetically and clinically heterogeneous. Despite advances in genetic testing, some patients remain undiagnosed, limiting targeted care. This study explores the genetic causes in Lithuanian patients with multiple kidney cysts. Genetic testing using kidney-focused next-generation sequencing or Sanger sequencing was performed on 114 patients. Genetic and clinical data from individuals with detected variants were analyzed. Diagnostic variants were identified in 69% of families; variants of uncertain significance in 13%, and the remaining families were undiagnosed. The diagnostic yield was 73% in Group 1 (defined cystic kidney phenotype) and 61% in Group 2 (nonspecific kidney cysts). In total, 24 novel variants were identified in seven genes. Autosomal dominant polycystic kidney disease (ADPKD) was the most common diagnosis. Among patients with nonspecific cysts, variants were found in PKD1, COL4A5, HNF1B, NPHP1, PAX2, TSC2, and UMOD, while 39% remained genetically unresolved. Patients with non-ADPKD diagnoses typically showed multiple cysts without a definitive phenotype. Most patients harbored disease-causing variants, with novel variants that will contribute to the ADPKD Variant Database. While ciliopathies are frequently recognized, genetic glomerulopathies may also present with a cystic phenotype. Genetic testing should be considered in cases of nonspecific multiple kidney cysts.
Tdrd12 is known to play an important role in spermatogenesis in mice. However, evidence linking TDRD12 mutations to male azoospermia is limited, and no cases of TDRD12-related teratozoospermia have been reported. We iden...Tdrd12 is known to play an important role in spermatogenesis in mice. However, evidence linking TDRD12 mutations to male azoospermia is limited, and no cases of TDRD12-related teratozoospermia have been reported. We identified two novel homozygous TDRD12 mutations (c.3378dupG and c.2463C>G) in two unrelated infertile men, respectively. Patient 1 carried a TDRD12 frameshift mutation (c.3378dupG), resulting in a truncated protein lacking the cysteine-rich domain. This patient presented with teratozoospermia, characterized by abnormal sperm morphology, including defects in the head and flagellum. Patient 2 carried a TDRD12 nonsense mutation (c.2463C>G), resulting in complete degradation of the protein. This patient exhibited azoospermia, characterized by germ cell maturation arrest at the spermatocyte stage. Mechanistically, TDRKH, TDRD9, PIWIL2, and PIWIL1, key piRNA biogenesis proteins, are predicted to interact with TDRD12. Notably, PIWIL1 fluorescence was reduced in Patient 1's sperm, while PIWIL2 and TDRD9 signals were diminished and LINE-1 signal was increased in Patient 2's testicular tissue. Furthermore, Intracytoplasmic sperm injection using Patient 1's sperm was unsuccessful. Our study first identified that the loss of different domains of TDRD12 results in distinct male infertility-related phenotypes. These findings revealed novel genetic insights into male infertility, demonstrated the critical role of TDRD12 in human spermatogenesis, and are helpful for diagnosis and genetic counseling.
Sudnawa KK, Geltzeiler A, Kanner CH
… +13 more, Zreibe K, Pini N, Tam C, Fee RJ, Calamia S, Callejo E, Sharples H, Serianni CE, Fagiolini M, Hanson E, Montes J, Levin A, Chung WK
Mitogen-activated protein kinase 8-interacting protein 3-related neurodevelopmental disorder (MAPK8IP3-related NDD) results from heterozygous pathogenic or likely pathogenic variants in MAPK8IP3. We report on 32 individu...Mitogen-activated protein kinase 8-interacting protein 3-related neurodevelopmental disorder (MAPK8IP3-related NDD) results from heterozygous pathogenic or likely pathogenic variants in MAPK8IP3. We report on 32 individuals (median age 7.5 years, range 1.3-22.0), all of whom had heterozygous pathogenic/likely pathogenic MAPK8IP3 variants, including missense (62.5%) and predicted loss-of-function (LOF) variants (34.4%). Common symptoms included cognitive impairment, hypotonia, motor difficulties, strabismus, microcephaly, and attention deficits. Corpus callosum thinning was reported in 62.1%. Nearly all individuals walked independently but demonstrated slower gait speed and a wider base of support compared to controls. The mean DAS-II General Conceptual Ability score was 62.5 ± 26.5. EEG analysis suggested a trend toward lower power accentuated frequency compared to typically developing individuals. Missense variants were associated with more severe symptoms than LOF variants. This study provides valuable insights into the clinical characteristics, patient management, and preparation for future clinical trials.
Neurodevelopmental disorders arising from mutations in RNA-processing factors are increasingly recognized but remain mechanistically underexplored. Here, we identify that variant (c.485A>C; p.Lys137Gln) in DDX39A in a 7-...Neurodevelopmental disorders arising from mutations in RNA-processing factors are increasingly recognized but remain mechanistically underexplored. Here, we identify that variant (c.485A>C; p.Lys137Gln) in DDX39A in a 7-month-old proband presenting with global developmental delay, microcephaly, seizures, hypotonia, and brain atrophy with corpus callosum thinning. DDX39A encodes a DEAD-box RNA helicase essential for mRNA splicing and export via the TREX complex. Functional studies in proband-derived fibroblasts revealed that while transcript and protein levels of DDX39A-K137Q were unaffected, the mutant protein displayed aberrant nuclear clumping and failed to interact with the TREX component THOC1. Structural modeling demonstrated that Lys137 mediates critical inter- and intra-molecular interactions, which are disrupted by the K137Q substitution. This loss destabilizes the DDX39A-THOC1 interface, impairing TREX complex integrity. The mutant cells exhibited severe nuclear morphological abnormalities, disrupted nuclear lamina organization, and increased cell death. Transcriptomic network analysis and gene ontology revealed enrichment of DDX39A interactions in mRNA export, splicing, and nucleocytoplasmic transport-functions essential for neuronal development. Temporal and regional brain expression data showed that DDX39A is highly expressed during early postnatal life and across multiple brain regions, indicating its importance in early brain maturation. Our findings establish DDX39A-K137Q as a pathogenic variant that impairs nuclear RNA processing and structural homeostasis, leading to a severe neurodegenerative phenotype. This study identifies the role of RNA helicases in neurodevelopment and explores DDX39A as a novel gene implicated in pediatric neurodegenerative disease.