RASopathies are a group of genetically heterogeneous developmental disorders caused by germline variants affecting the RAS/MAPK signaling pathway. These disorders display overlapping clinical features and diverse molecul...RASopathies are a group of genetically heterogeneous developmental disorders caused by germline variants affecting the RAS/MAPK signaling pathway. These disorders display overlapping clinical features and diverse molecular mechanisms. This study aimed to evaluate the clinical and molecular spectrum of patients diagnosed with RASopathies, with a particular focus on novel and rare variants. A retrospective, multicenter study was conducted on patients with clinically suspected RASopathy and diagnosed by targeted Next Generation Sequencing analysis between 2021 and 2024. Variants were classified according to ACMG criteria, and clinical data were reviewed for genotype-phenotype correlations. Among 23 patients (14 males, 9 females), 15 (65.2%) had Noonan syndrome, five (21.7%) Neurofibromatosis Type 1, two (8.7%) Cardio-facio-cutaneous syndrome, and one (4.3%) Neurofibromatosis-Noonan syndrome. The most frequent clinical findings were craniofacial dysmorphism (91.3%), musculoskeletal anomalies (82.6%), and cutaneous features (78.3%). A total of 24 heterozygous variants were identified in seven genes: PTPN11 (45.8%), NF1 (25%), LZTR1 (12.5%), and RASA2, SOS1, MAP2K1, and BRAF (each 4.2%). Four novel variants were detected (PTPN11 c.853 + 4A>G, RASA2 p.E71D, NF1 p.W784Mfs*10, MAP2K1 p.A106T). This study highlights the clinical and molecular heterogeneity of RASopathies and expands the variant spectrum with novel and rare pathogenic alterations. The identification of new variants, particularly in rarely implicated genes such as RASA2, underlines the diagnostic value of comprehensive NGS-based testing and the need for individualized, multidisciplinary clinical management.
Chaabouni M, Miladi N, Monastiri K
… +11 more, Kraoua I, Mrabet H, Mrabet A, Bezzine NB, Jabnoun S, Chouikh FZ, Nouaili N, Dabbabi A, Turki I, Farhat E, Bouhamed-Chaabouni H
Although exome sequencing (ES) is not widely implemented in some countries due to financial constraints, it represents an effective approach for the genetic diagnosis of neurodevelopmental disorders (NDDs). We report ES...Although exome sequencing (ES) is not widely implemented in some countries due to financial constraints, it represents an effective approach for the genetic diagnosis of neurodevelopmental disorders (NDDs). We report ES results from a North African cohort of 168 unrelated patients with NDDs referred for diagnostic testing. Patients were classified into three clinical categories: isolated NDDs (29%), NDDs associated with epilepsy (17%), and NDDs with dysmorphic features (54%). The consanguinity rate was 63%. ES identified pathogenic or likely pathogenic variants (71 SNVs and 5 CNVs) in 75 patients, corresponding to a diagnostic yield of 45%. Variants of uncertain significance were detected in 66 cases (39%). Among pathogenic/likely pathogenic findings, variants were predominantly homozygous (39 out of 42 autosomal recessive cases), followed by heterozygous variants associated with autosomal dominant inheritance (29 cases) and hemizygous X-linked variants (5 cases). In conclusion, ES demonstrated a high diagnostic yield in this cohort, supporting its value as a diagnostic tool for NDDs, particularly in highly consanguineous populations.
We report a rare family of optic atrophy diseases associated with mitochondrial DNA G8363A transfer ribonucleic acid (RNA) cleavage mutations. This family does not exhibit the characteristic symptoms of myoclonic epileps...We report a rare family of optic atrophy diseases associated with mitochondrial DNA G8363A transfer ribonucleic acid (RNA) cleavage mutations. This family does not exhibit the characteristic symptoms of myoclonic epilepsy or cutaneous lipomas, but instead presents with bilateral optic atrophy. The clinical presentation in this family is highly atypical compared to previous reports.
Caramizaru A, Durac C, Dumitrescu A
… +14 more, Calota-Dobrescu A, de Becdelièvre A, Konyukh M, Cassandrini D, Lee H, Seo GH, Ryu SW, Cucu M, Dragomir IM, Catana A, Tajsharghi H, Malfatti E, Burada F, Dobrescu A
Neurodevelopmental disorders (NDDs) are a highly diverse group of conditions that manifest through motor, cognitive, and behavioral impairments, representing the most common chronic condition encountered in children. As...Neurodevelopmental disorders (NDDs) are a highly diverse group of conditions that manifest through motor, cognitive, and behavioral impairments, representing the most common chronic condition encountered in children. As these often have a genetic cause or component, extensive genetic testing, particularly whole exome sequencing (WES), plays a critical role in their diagnosis, management, and prevention. Here, we present detailed clinical and genetic data on 54 Romanian patients included in the NeuroMyoDredger project, and provide an overview of the current landscape of genetic testing availability for NDDs in Romania, commenting on current barriers and the importance of integrating advanced genomic technologies into national healthcare strategies. A total of 54 undiagnosed Romanian patients with an initial clinical suspicion of unspecific NDD have benefited from singleton WES (including CNV and mitochondrial DNA analysis), with a diagnostic yield of 50%. Furthermore, a substantial proportion of cases (eight patients, 14.81%) yielded nondefinitive results involving variants of uncertain significance, with potential pathogenic relevance. Our findings align with the existing literature data, supporting the integration of singleton WES with CNV and mitochondrial variants detection as a first-line investigation in the diagnostic workflow for NDDs.
XPR1 encodes the only known phosphate exporter in human cells and regulates the export of inorganic phosphate (Pi). To date, heterozygous pathogenic variants have been reported to be associated with autosomal-dominant id...XPR1 encodes the only known phosphate exporter in human cells and regulates the export of inorganic phosphate (Pi). To date, heterozygous pathogenic variants have been reported to be associated with autosomal-dominant idiopathic basal ganglia calcification-6 (IBGC6; MIM: 616413). We collate clinical information on individuals with biallelic XPR1 variants and use in silico and cell-based studies to evaluate pathogenicity. Four consanguineous families have been documented, with a severe neonatal phenotype presenting with persistent pulmonary hypertension, chronic lung disease, cardiomyopathy, and hypophosphatemia. Affected individuals exhibit microcephaly, intracranial calcifications, and profound neurodevelopmental impairment; the prognosis is generally poor. Exome and Sanger sequencing confirmed segregation with homozygosity for a rare, likely deleterious, biallelic XPR1 variant NM_004736.4: c.1811G>A: p.Arg604Gln. Analysis of primary cell lines showed stable expression of the XPR1 protein. In silico structural analysis supported the variant's deleterious nature. Published mutagenesis studies demonstrate that mutations at the arginine residue (Arg604) within the second putative Pi coordination site substantially impair Pi export in functional flux assays. This study establishes a link between a novel severe neonatal disease and specific biallelic variants in XPR1 that result in a loss-of-function phenotype.
A deep-intronic single nucleotide variant in RUNX2 causes the characteristic clinical features of cleidocranial dysplasia (CCD) in a family via pseudo-exon inclusion into the mRNA. The pseudo-exon contains a premature st...A deep-intronic single nucleotide variant in RUNX2 causes the characteristic clinical features of cleidocranial dysplasia (CCD) in a family via pseudo-exon inclusion into the mRNA. The pseudo-exon contains a premature stop codon and triggers mRNA decay, which results in RUNX2 haploinsufficiency, the known disease mechanism.
Smith E, Faundes V, Zhao X
… +13 more, Zheng B, Zhang G, Mao X, Danko E, Laufman J, Besnard T, Isidor B, Cogné B, Jensson BÖ, Sulem TS, Sulem P, Rosenfeld JA, Scott DA
WD and tetratricopeptide repeats protein 1 (WDTC1) encodes a component of the cullin-RING E3 ligase complexes that mediate polyubiquitination of specific target proteins for degradation and has been shown to regulate lip...WD and tetratricopeptide repeats protein 1 (WDTC1) encodes a component of the cullin-RING E3 ligase complexes that mediate polyubiquitination of specific target proteins for degradation and has been shown to regulate lipid storage in studies performed in Drosophila, mice, and humans. WDTC1 is expressed in a wide variety of tissues and organs including the brain and is predicted to be loss-of-function intolerant. To determine the phenotypes associated with WDTC1 haploinsufficiency, we identified seven individuals, six of whom have not been previously reported, who are heterozygous for loss-of-function or putatively damaging missense variants in WDTC1. None of these individuals were reported to be obese, but all had neurodevelopmental phenotypes that included developmental delay and intellectual disability. Seizures were also recurrently reported. One loss-of-function variant was inherited from an affected mother, and one missense variant was inherited from an unaffected father. Our findings suggest that WDTC1 haploinsufficiency causes a neurodevelopmental syndrome characterized by variable developmental delay, intellectual disability, and seizures. The identification of additional patients with loss-of-function variants will be needed to identify recurrent patterns of less common phenotypes, determine with greater certainty if obesity is or is not a feature associated with this disorder, and confirm that this disorder is incompletely penetrant.
Marfan syndrome is a heritable connective tissue disorder characterized by multisystem involvement, particularly affecting the skeleton. We performed an iconodiagnostic evaluation of the Etruscan bronze statue "L'Ombra d...Marfan syndrome is a heritable connective tissue disorder characterized by multisystem involvement, particularly affecting the skeleton. We performed an iconodiagnostic evaluation of the Etruscan bronze statue "L'Ombra della Sera" to assess whether its morphological features may reflect a real connective tissue phenotype rather than symbolic elongation. Systemic features were evaluated according to the revised Ghent nosology. The statue exhibits disproportionate longitudinal growth, thoracic deformities, craniofacial characteristics, and pedal findings consistent with a systemic connective tissue phenotype. Although limitations inherent to artistic representation must be considered, the overall morphological pattern is compatible with a MASS-Marfan spectrum phenotype. This study highlights the potential contribution of iconodiagnosis to the historical investigation of genetic disorders.
KBG syndrome (KBGS, OMIM #148050) is a rare genetic disorder caused by heterozygous truncating or missense variants in the ANKRD11 gene or a deletion of 16q24.3 involving ANKRD11. While truncating variants clearly disrup...KBG syndrome (KBGS, OMIM #148050) is a rare genetic disorder caused by heterozygous truncating or missense variants in the ANKRD11 gene or a deletion of 16q24.3 involving ANKRD11. While truncating variants clearly disrupt protein function, the interpretation of missense variants is more challenging, as many remain variants of uncertain significance (VUS). To address this, we evaluated PhenoScore, an open-source AI-based phenomics framework integrating facial recognition and medical data analysis, for predicting the pathogenicity of ANKRD11 missense variants and providing supporting evidence for variant interpretation within the ACMG framework, specifically the PP4 criterion. PhenoScore was trained on 79 individuals with truncating variants in ANKRD11 and age-, sex-, and ethnicity-matched controls with other neurodevelopmental disorders, and its performance was compared to AlphaMissense, REVEL, and the evaluation of a clinical geneticist. Six individuals with functionally confirmed pathogenic missense variants were used for testing. PhenoScore achieved high predictive accuracy with an area under the curve (AUC) of 0.95 and a Brier score of 0.089, and pathogenic missense variants in the test set received a mean prediction score of 0.94. PhenoScore significantly outperformed REVEL (p < 0.01), especially in cases supported by functional and clinical evidence, while no significant difference was observed compared to AlphaMissense (p = 0.63); importantly, the two tools showed complementary strengths. These findings suggest that PhenoScore represents a promising tool for clinical variant interpretation, as it quantifies phenotypic concordance with KBGS and provides objective evidence that can strengthen the PP4 criterion within the ACMG framework. Combined with molecular prediction tools like AlphaMissense, PhenoScore may help reduce uncertainty surrounding VUS in ANKRD11 by complementing these scores.
Cellular homeostasis is maintained by deubiquitination, which plays critical roles in DNA damage repair, cell cycle progression, signal transduction, transcriptional regulation, and autophagy. The deubiquitination (DUB)...Cellular homeostasis is maintained by deubiquitination, which plays critical roles in DNA damage repair, cell cycle progression, signal transduction, transcriptional regulation, and autophagy. The deubiquitination (DUB) module within the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex is encoded by the ATXN7L3 gene. Disease-causing variants in ATXN7L3 have been associated with an autosomal dominant neurodevelopmental disorder characterized by global developmental delay, hypotonia, speech impairment, and distinctive facial dysmorphism, known as Harel-Tora neurodevelopmental syndrome (OMIM #621377). In the present study we used whole-genome sequencing (WGS), followed by Sanger sequencing, to identify the disease-causing genetic variant. WGS identified a novel de novo nonsense variant, c.236G>A (p.Trp79*), in the exon 4 of the ATXN7L3 gene (NM_001382309.1) located on chromosome 17q21.31, segregating perfectly with the disease phenotype. Furthermore, RT-qPCR revealed a marked reduction in ATXN7L3 transcript levels in the affected individual, supporting its pathogenicity. 3D protein modeling of the mutated ATXN7L3 protein revealed substantial distortions in key secondary structural elements and loss of the C-terminal of ATXN7L3. The present study expands the mutational spectrum of the ATXN7L3 gene associated with HATONS, and helps to provide accurate genetic counseling. This will help in the management of future pregnancies within the affected family.
Dandy-Walker malformation (DWM) is a rare congenital abnormality of the posterior fossa and the cerebellum and has an incidence of 1 in 10 000 to 30 000 births. Although DWM can present in isolation, it is often associat...Dandy-Walker malformation (DWM) is a rare congenital abnormality of the posterior fossa and the cerebellum and has an incidence of 1 in 10 000 to 30 000 births. Although DWM can present in isolation, it is often associated with other central nervous system (CNS) abnormalities or extra-CNS anomalies (DWM+). A molecular cause is not identified in the majority of individuals with DWM+. This is due, in part, to uncertainty regarding optimal testing strategies and an incomplete understanding of the genetic causes of DWM+. In this study, we analyzed clinical exome sequencing (cES) data from 91 individuals with DWM+ to determine its diagnostic efficacy. A definitive or probable diagnosis was made for 32 individuals, yielding a diagnostic rate of 35.2% (32/91). Commercially available brain malformation panels would have detected only 24.2% (8/33) to 54.5% (18/33) of the diagnoses made by cES. We then used data from our cohort, published cases, and mouse models to identify nine phenotypic expansions involving DWM. Our results suggest that cES should be considered for all individuals with DWM+ for whom a molecular diagnosis has not been established and that additional testing to identify a genetic cause of DWM is likely not warranted in individuals with genetic syndromes caused by variants in ANKRD11, C2CD3, COL4A1, KMT2D, KRAS, OPHN1, SHOC2, SMARCB1, and WDR73.
Hong J, Lee S, Kim SY
… +18 more, Kim T, Shin WH, Jang S, Park JH, Jang D, Park G, Cha JH, Cho JS, Cho A, Kim H, Woo H, Kim JS, Lim BC, Lee JE, Kim M, Cheon CK, Choi J, Chae JH
Neurodevelopmental disorders (NDDs) often remain unexplained due to limited assessment of non-coding genomic elements. Motivated by recent reports implicating RNU4-2, which encodes a spliceosomal small nuclear RNA (snRNA...Neurodevelopmental disorders (NDDs) often remain unexplained due to limited assessment of non-coding genomic elements. Motivated by recent reports implicating RNU4-2, which encodes a spliceosomal small nuclear RNA (snRNA), we analyzed whole-genome sequencing data from 15 450 Korean individuals, including 2797 unrelated NDD probands. Rare pathogenic RNU4-2 variants were identified in 20 probands (0.72%), including 17 (85%) with a recurrent n.64_65insT variant. RNA secondary structure modeling and molecular dynamics simulations demonstrated that n.64_65insT disrupts the U4/U6 snRNA duplex and impairs exposure of the U6 ACAGAGA motif required for 5' splice-site recognition. Whole-blood RNA-seq from carriers revealed increased alternative 5' splice-site usage and dysregulation of immune, chromosomal, and DNA metabolic gene programs. Clinically, affected individuals presented with global developmental delay, microcephaly, seizures, failure to thrive, and dysmorphic features. These findings establish RNU4-2, particularly n.64_65insT, as a cause of early-onset NDD. We advocate for routine assessment of spliceosomal RNA genes in genomic diagnostics and reanalysis of unsolved cases to improve yield and guide counseling in rare neurodevelopmental syndromes.
Direct to consumer genetic testing (DTC-GT) has expanded exponentially in the past decade, but little is known about Genetic Health Practitioners' (GHPs') experience with, attitudes towards, and capacity to support DTC-G...Direct to consumer genetic testing (DTC-GT) has expanded exponentially in the past decade, but little is known about Genetic Health Practitioners' (GHPs') experience with, attitudes towards, and capacity to support DTC-GT consumers. This scoping review aimed to consolidate empirical research to understand GHP and consumer needs and identify knowledge gaps. Forty-four publications from 2007 to 2025 covering GHP attitudes towards DTC-GT and GHP/consumer experiences of counselling (n = 30); company provision of counselling (n = 12); and counsellor-designed tools for DTC-GT consumers (n = 2) were reviewed. Of studies reporting GHP attitudes and experiences, the majority (82%) focused on GHPs in clinical settings. GHPs considered counselling necessary for informed consent and result interpretation, but felt this was outside their professional responsibilities, wanted additional resources and clearer practice guidelines. Despite considering counselling the responsibility of the DTC-GT companies, many GHPs were concerned about inherent conflicts of interest and wanted greater industry oversight and regulation. Little literature on the extent of company-provided counselling (n = 12) was identified, and none on quality. This review highlights the need to clarify the roles and scope of GHPs in clinical practice regarding DTC-GT, to develop best-practice models, and for more research on the nature and efficacy of counselling by GHPs in company and non-clinical settings.
Pediatric dilated cardiomyopathy (DCM) carries high morbidity and mortality, with up to half of cases genetically unexplained. The mTORC1 nutrient sensing pathway is a critical regulator of cardiomyocyte homeostasis, yet...Pediatric dilated cardiomyopathy (DCM) carries high morbidity and mortality, with up to half of cases genetically unexplained. The mTORC1 nutrient sensing pathway is a critical regulator of cardiomyocyte homeostasis, yet no Mendelian DCM genes have been linked to its upstream regulator, GATOR2. WDR59 encodes a core WD-repeat subunit of GATOR2, but its cardiac role is unknown. We recruited six affected individuals from four unrelated families presenting with early-onset, severe autosomal recessive syndromic DCM. Affected children developed left ventricular dilation, variably accompanied by cataracts, dysmorphic facial features, and growth and developmental delay. Saudi patients mapped to a single locus and shared therein a homozygous founder WDR59 variant: c.2887G>A (p.Gly963Arg). The French patient was compound heterozygous for two variants (NM_030581.4:c.966+3A>G and NM_030581.4:c.886+1219T>G) and their deleterious splicing effect was confirmed by RNA-seq. We propose WDR59 as a novel autosomal recessive DCM gene and implicate dysregulated GATOR2-mTORC1 signaling as the underlying mechanism. Future validation is needed to confirm this link and investigate whether restoring mTORC1-autophagy balance can ameliorate WDR59-related cardiac dysfunction.
Phelan-McDermid syndrome (PMS) frequently presents with distinctive facial features, although a typical facial phenotype for this condition has not been well characterized. Facial dysmorphology assessments can be subject...Phelan-McDermid syndrome (PMS) frequently presents with distinctive facial features, although a typical facial phenotype for this condition has not been well characterized. Facial dysmorphology assessments can be subjective, depending on the experience and training of the clinical geneticist conducting the patient evaluation. In this investigation, we sought to quantitatively assess craniofacial features in Phelan-McDermid syndrome. Three-dimension (3D) morphometric assessment was conducted of 100 children and young adults diagnosed with PMS and 536 age- and sex-matched typically developing subjects obtained from the FaceBase consortium. The data were analyzed using principal component analysis (PCA), Procrustes MANOVA, and canonical variates analysis (CVA). We found that people with PMS aged 3-32 years have quantitatively distinctive craniofacial features compared to age- and sex-matched normed people. We observed an elongated face, a pointed chin, a flattened midface, and nasal expansion as characteristic of the PMS facial phenotype. Further, distinct growth patterns were observed, with children ages 3-6 and 7-12 years having more rapid growth compared to matched normed samples. While people with PMS have distinctive facial features, individual variation is the greatest contribution to facial variation. Quantitative assessment of craniofacial features paired with genotype can further our understanding of genetic contributions to craniofacial development.
Recent advances in epilepsy genetics have revolutionized the diagnosis and management of patients. This study was conducted to evaluate the clinical significance of molecular diagnosis in Egyptian patients with pediatric...Recent advances in epilepsy genetics have revolutionized the diagnosis and management of patients. This study was conducted to evaluate the clinical significance of molecular diagnosis in Egyptian patients with pediatric-onset drug-resistant epilepsy (DRE). All patients lacked electro-clinic-radiological concordant lesions and therefore were not candidates for surgical intervention. More than 70% of cases had variable degrees of cognitive impairment, and about 25% had different forms of movement disorders. Exome sequencing was able to unravel potential genetic defects in 40 patients across 31 genes. The study identified 15 novel variants, including those in MYCBP2 and BAZ2B, which were recently linked to genetic epilepsy. Genetic diagnosis refined classification and guided therapy in several patients, particularly those with ion channelopathies, progressive myoclonic epilepsy, infantile convulsions, choreoathetosis syndrome, and glucose transporter Type 1 deficiency. Our findings underscore the importance of genetic testing for patients with DRE, improving clinical classifications beyond electroclinical assessments and supporting better outcomes.
Pathogenic variants in GINS1 are believed to cause a primary combined immunodeficiency and growth retardation syndrome with natural killer cell deficiency and chronic neutropenia. To date, however, very few cases have be...Pathogenic variants in GINS1 are believed to cause a primary combined immunodeficiency and growth retardation syndrome with natural killer cell deficiency and chronic neutropenia. To date, however, very few cases have been reported. Thus, the role of GINS1 in disease, as well as the spectrum of variants and their associated phenotype, remains unclear. We present a 2-year-old female with growth retardation, chronic neutropenia, distinctive facial features, and glaucoma. Exome sequencing revealed two likely pathogenic variants in GINS1, c.-48C>G p.? and c.247C>T p.Arg83Cys, conferring a diagnosis of GINS1 deficiency. She has overlapping features with the previously reported individuals, cementing growth retardation, neutropenia, and natural killer cell deficiency as core features. We additionally present a review of all nine individuals reported to date. We highlight that our proband, unlike the others, has no history of infections, and that glaucoma has now been observed in multiple unrelated individuals, pointing toward possible phenotypic expansion. Efforts to identify affected individuals, including those with different variants and phenotypes, are needed to understand ways in which GINS1 may be implicated in disease and the phenotypic spectrum of this ultrarare inborn error of immunity.
Accurate parental haplotype information is crucial for noninvasive prenatal diagnosis (NIPD) of recessive single-gene disorders (SGD) (NIPD-SGD). However, conventional approaches rely on complex experimental techniques o...Accurate parental haplotype information is crucial for noninvasive prenatal diagnosis (NIPD) of recessive single-gene disorders (SGD) (NIPD-SGD). However, conventional approaches rely on complex experimental techniques or trio-based SNP linkage analysis requiring family members, which limit clinical application. Here, we present a novel direct haplotyping based NIPD approach termed DiHNIPD, utilizing single-tube long fragment read (stLFR) sequencing. First, parental genome-wide haplotypes were reconstructed by stLFR-based whole genome sequencing (WGS). Second, SNPs within and surrounding the target gene in maternal plasma were identified by WGS. Finally, fetal haplotypes were determined by implementing a parental haplotype-assisted hidden Markov model combined with the Viterbi algorithm. The DiHNIPD results were further confirmed by invasive prenatal diagnosis. This study recruited 23 couples at risk of having a fetus with SGD. DiHNIPD directly phased all parental haplotypes of the target gene and accurately deduced 23 fetal genotypes, achieving 100% concordance with diagnostic results. These results demonstrate that DiHNIPD is a sensitive, user-friendly and inexpensive strategy for NIPD-SGD. It eliminates the need for expensive devices and complex procedures and does not rely on family members. This method shows significant promise for clinical use in high-risk pregnancies without prior offspring.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency exhibits high prevalence in malaria-endemic regions and areas along the historic Maritime Silk Road. This study investigated the burden and genetic architecture of G6PD...Glucose-6-phosphate dehydrogenase (G6PD) deficiency exhibits high prevalence in malaria-endemic regions and areas along the historic Maritime Silk Road. This study investigated the burden and genetic architecture of G6PD deficiency in Nanning, the ethnically diverse capital of Guangxi in southern China, where Southeast Asian gene flow has shaped population genetics. We screened 14 403 individuals for G6PD activity at The First Affiliated Hospital of Guangxi Medical University, defining deficiency as activity < 60% of adjusted male median (AMM = 2045 U/L). Among 2513 deficient cases (prevalence: 17.45%), frequency was significantly higher in males (63.75%) vs. females (36.25%; p < 0.001) and Han Chinese (60.92%) vs. Zhuang (39.08%; p = 0.925). Multiplex melting curve analysis (MMCA) of 2513 enzyme-deficient samples identified pathogenic mutations in 1161 cases, revealing 13 distinct variants. The predominant mutations were: c.1388G>A (39.53%; 459/1161), c.1376G>T (24.81%; 288/1161), and c.95A>G (12.40%; 144/1161). Mutation c.871G>A exhibited male bias (p < 0.001), while c.95A>G was Zhuang-enriched (p < 0.001). Sanger sequencing of MMCA-negative cases identified two rare pathogenic variants (c.406C>T, c.196T>A). Our findings establish Nanning as a region of exceptionally high G6PD deficiency prevalence and delineate a distinct mutation profile with sex- and ethnicity-linked distributions. These results provide critical insights for designing precision screening programs and public health strategies tailored to this genetically diverse population.
Chiriatti L, Priolo M, Leoni C
… +16 more, Onesimo R, Carvetta M, Parrino M, Tamburrini G, Contaldo I, Russo R, Friedman J, Rogan S, Ciolfi A, Ferilli M, Cappelletti C, Niceta M, Radio FC, Mancini C, Tartaglia M, Zampino G
UBTF codes for a nucleolar transcription factor required for transcription of rDNA genes. UBTF gain-of-function (GoF) has been identified as the cause of CONDBA syndrome, with a recurrent missense change, p.Glu210Lys occ...UBTF codes for a nucleolar transcription factor required for transcription of rDNA genes. UBTF gain-of-function (GoF) has been identified as the cause of CONDBA syndrome, with a recurrent missense change, p.Glu210Lys occurring in most affected individuals. More recently, eight subjects with truncating variants or microdeletions involving UBTF have been associated with a distinct neurodevelopmental disorder in which developmental delay (DD) and intellectual disability (ID) co-occur with behavioral anomalies in the absence of signs of neuroregression. Here, we report on four affected individuals, including one adult subject, from a single family carrying a heterozygous UBTF splice-site variant affecting transcript processing. All subjects presented with a clinical phenotype characterized by DD/ID with behavioral problems, without signs of neuroregression. By systematically examining the clinical features in both current and previously reported cases, we identify a characteristic facial gestalt as a hallmark of the disorder, and recognize increased BMI and a hyper-nasal voice as previously underappreciated features. These data provide further evidence that UBTF haploinsufficiency causes a non-regressive form of DD/ID clinically distinct from CONDBA syndrome.