Noonan syndrome (NS) and related RASopathies form a clinically and genetically heterogeneous group of disorders caused by germline dysregulation of the RAS/MAPK pathway. Pathogenic variants in PTPN11 account for roughly...Noonan syndrome (NS) and related RASopathies form a clinically and genetically heterogeneous group of disorders caused by germline dysregulation of the RAS/MAPK pathway. Pathogenic variants in PTPN11 account for roughly half of classical NS, but the contribution of non-PTPN11 genes in patients referred with NS or Noonan-like phenotypes remains incompletely defined in several populations, including Russia. We characterized the spectrum of non-PTPN11 variants in a large Russian cohort referred for suspected NS or Noonan-like phenotypes and examined gene-specific clinical patterns. We analyzed 456 unrelated patients with clinically diagnosed NS or Noonan-related syndromes using a targeted panel of 23 RAS/MAPK pathway genes. PTPN11 variants (23% of cases) were reported previously; here we focused on the remaining patients. Pathogenic or likely pathogenic variants were identified in 19% of cases (85/456), with NF1, SOS1, SHOC2, and BRAF being the most frequently mutated genes, together accounting for 50% of the non-PTPN11 diagnoses. Novel variants were observed in 12.1% of cases (7/58 unique variants). Several genotype-phenotype associations emerged: SOS1 mutations were associated with a high prevalence of cardiac defects, especially pulmonary stenosis and atrial septal defects (64% of patients, p = 0.01), whereas NF1 and SPRED1 cases had significantly fewer cardiac anomalies (p < 0.001 and p < 0.05, respectively). Lentigines were predominantly seen in NF1 and SPRED1 patients (p < 0.01), and all three evaluable males with MAP2K1 variants had cryptorchidism (3/3). Conversely, BRAF-mutated patients showed lower incidence of chest deformity (p < 0.01) but higher rates of developmental delay. NF1, SOS1, SHOC2, and BRAF together accounted for half of the non-PTPN11 molecular diagnoses in this Russian cohort, and the observed gene-specific clinical patterns align with previous series, although limited subgroup sizes preclude firm individual associations.
PACS1 neurodevelopmental disorder (PACS1-NDD), also known as Schuurs-Hoeijmakers syndrome, is a rare genetic condition caused by a recurrent de novo mutation in the PACS1 gene. Autistic traits have been reported in PACS1...PACS1 neurodevelopmental disorder (PACS1-NDD), also known as Schuurs-Hoeijmakers syndrome, is a rare genetic condition caused by a recurrent de novo mutation in the PACS1 gene. Autistic traits have been reported in PACS1-NDD, but systematic longitudinal assessments are lacking. We followed five children (3 females) with genetically confirmed PACS1-NDD, aged 1.4-6.2 years at entry, over 2-3.5 years (29 assessments). Measures included standardized behavioral and cognitive assessments, eye-tracking, and structural MRI. Data were compared to 357 autistic and 123 typically developing children from a longitudinal cohort. Children with PACS1-NDD showed global developmental delays with heterogeneous trajectories. Adaptive and communication profiles overlapped with autistic children, while motor impairments were more pronounced. Vocabulary and grammar were delayed, but pragmatic skills were relatively preserved. All children with PACS1-NDD exhibited autistic traits with elevated restricted and repetitive behaviors and milder social-communication difficulties. ADHD symptoms were subthreshold and predominantly inattentive. Eye-tracking revealed preserved social interest but reduced gaze typicality in naturalistic contexts. MRI showed globally reduced gray and white matter volumes. These findings provide the first longitudinal, multimodal characterization of PACS1-NDD, informing clinical care and targeted outcome measures for therapeutic trials, and highlighting the need for larger studies to validate and extend these findings.
Pathogenic variants in AMMECR1 have been associated with a rare multisystem disorder characterized by midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MFHIEN). To date, most reported cases in...Pathogenic variants in AMMECR1 have been associated with a rare multisystem disorder characterized by midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MFHIEN). To date, most reported cases involve copy number variants or presumed loss-of-function alterations, with only a single prior report describing a missense variant supported by functional studies. Here, we report a patient with a heterozygous de novo AMMECR1 missense variant, NM_015365.3:c.649G>A p.(Val217Met) presenting with clinical features consistent with MFHIEN, including midface hypoplasia, partial hearing impairment, nephrocalcinosis, and elliptocytosis identified on peripheral blood smear. Comparative review of the literature highlights that while previously reported missense variants in AMMECR1 demonstrated altered intranuclear protein distribution and reduced expression in functional assays, clinical evidence supporting pathogenicity of non-truncating variants remains limited. The phenotypic overlap between our patient and prior report strengthens the association between missense variations and the MFHIEN phenotype. Our findings support the pathogenic relevance of missense variation in AMMECR1 and emphasize the importance of integrating detailed phenotyping, including hematologic evaluation, with genomic data in the diagnosis of rare multisystem disorders. Additional cases and functional studies are needed to clarify genotype-phenotype correlations and underlying disease mechanisms.
Pathogenicity predictors exceed AUROC 0.97 on expert-curated ClinVar, yet the monogenic-epilepsy variant-of-uncertain-significance backlog persists because pathogenicity alone provides no direction-of-effect, no scalable...Pathogenicity predictors exceed AUROC 0.97 on expert-curated ClinVar, yet the monogenic-epilepsy variant-of-uncertain-significance backlog persists because pathogenicity alone provides no direction-of-effect, no scalable mechanism-to-treatment mapping, and no evidence that updates as ClinVar grows. SeizeVar couples a consensus pathogenicity head (random forest plus ESM-2 LoRA cross-attention) to a gain-versus-loss-of-function mechanism classifier and a deterministic sodium-channel mechanism-direction rule. The framework was trained on a 49-gene epilepsy panel (n = 4576 labelled variants) and evaluated on six pairwise-disjoint held-out cohorts (n = 11 274) plus an external functional cohort with patch-clamp/TEVC labels (T2, n = 415). SeizeVar's mechanism head reaches honest leave-one-gene-out AUROC = 0.736 at 100% panel coverage and matches the proteome-wide specialist LoGoFunc on fair full-coverage comparison (0.770 vs. 0.760), whereas general-purpose pathogenicity predictors are mechanism-blind (AUROC ≤ 0.62). Applied to 29 293 epilepsy VUS, the pipeline returned 4708 consensus Likely-Pathogenic candidates, of which 1500 sodium-channel variants received predicted mechanism-direction labels (679 LoF-leaning, 821 GoF-leaning). By integrating pathogenicity, mechanism, and dynamic evidence on a shared probability scale, SeizeVar produces a mechanism-annotated prioritisation list to support-not replace-expert variant curation; the outputs are computational predictions and a natural next step is prospective clinical validation. Reclassified-VUS is released as a community benchmark for reclassification-aware evaluation.
Male infertility, often caused by structural and functional sperm defects, remains genetically unexplained in a substantial proportion of cases. ATP1A4 encodes a testis-specific isoform of the Na, K-ATPase, a membrane en...Male infertility, often caused by structural and functional sperm defects, remains genetically unexplained in a substantial proportion of cases. ATP1A4 encodes a testis-specific isoform of the Na, K-ATPase, a membrane enzyme crucial for maintaining cellular ionic homeostasis. Previous studies on Atp1a4 knockout mice have demonstrated severe defects in sperm motility and flagellar architecture; however, the contribution of ATP1A4 variants to human male reproduction remains to be elucidated. In this study, we identified compound biallelic variants in ATP1A4, a missense variant (c.2578 T>A, p.Tyr860Asn) and a frameshift variant (c.2582del, p.Gly861Aspfs*5), in a patient presenting with severe oligoasthenoteratozoospermia. Both variants markedly affected ATP1A4 protein expression. Morphological analyses revealed coiled and folded flagella, disrupted mitochondrial sheaths, and irregular head morphology in the patient's spermatozoa. Expression profiling revealed that ATP1A4 was highly enriched in post-meiotic spermatids and localized along the entire flagellum of mature sperm in both humans and mice, indicating a critical role in flagellar assembly and structural integrity. Notably, intracytoplasmic sperm injection (ICSI) in this patient resulted in low fertilization efficiency and failed implantation, suggesting a potential adverse impact of ATP1A4 deficiency on sperm functional competence beyond motility. These findings broaden the genetic spectrum of oligoasthenoteratozoospermia and highlight ATP1A4 as a potential gene associated with human male infertility.
Hereditary optic atrophy is characterized by degeneration of retinal ganglion cells and may result from a wide range of genetic etiologies. While pathogenic variants in OPA1 and primary mitochondrial variants causing Leb...Hereditary optic atrophy is characterized by degeneration of retinal ganglion cells and may result from a wide range of genetic etiologies. While pathogenic variants in OPA1 and primary mitochondrial variants causing Leber hereditary optic neuropathy (LHON) account for a substantial proportion of cases, many patients remain genetically unsolved. We evaluated the diagnostic yield and clinical impact of comprehensive whole exome/genome sequencing (WES/WGS)-based virtual panel testing in 62 partially pre-screened individuals with suspected hereditary optic atrophy. A total of 51 genes associated with optic atrophy and mitochondrial DNA variants were analyzed. Clinical data were systematically retrieved from medical records, including information on extraocular manifestations. A genetic diagnosis was established in 21 patients (33.9%). Pathogenic or likely pathogenic variants in OPA1 accounted for 57.1% of solved cases, whereas 42.9% involved other genes, including WFS1, ACO2, NR2F1, UCHL1, CACNA1F, and COQ2. In the majority of patients with non-OPA1 findings, the genetic diagnosis prompted additional clinical evaluation, surveillance, or therapeutic intervention. Our findings demonstrate that broad WES/WGS-based testing increases diagnostic yield and expands the genetic spectrum beyond OPA1 and LHON, frequently revealing syndromic conditions with direct clinical implications. Comprehensive genomic testing with broader gene panels should therefore be considered part of the diagnostic workup when hereditary optic atrophy is suspected.
Severe congenital neutropenia (SCN) is a genetically heterogeneous condition. Reaching a molecular diagnosis is important for management, prognostication, and risk assessment. We present the first confirmatory report of...Severe congenital neutropenia (SCN) is a genetically heterogeneous condition. Reaching a molecular diagnosis is important for management, prognostication, and risk assessment. We present the first confirmatory report of a previously proposed SCN due to a homozygous pathogenic loss-of-function variant in CSF3. Our report supports this new gene-disease relationship in humans.
Graphical abstract illustrating the clinical presentation, molecular mechanism, and diagnostic implications of biallelic TMEM126B variants associated with progressive kidney disease. The case involved a 47-year-old male...Graphical abstract illustrating the clinical presentation, molecular mechanism, and diagnostic implications of biallelic TMEM126B variants associated with progressive kidney disease. The case involved a 47-year-old male with childhood exercise intolerance, possible hypertrophic cardiomyopathy, and progressive kidney failure. Initial comprehensive inherited kidney disease panel testing was nondiagnostic; subsequent updated exome sequencing identified a homozygous TMEM126B variant (c.635G>T; p.Gly212Val). TMEM126B encodes a mitochondrial complex I assembly factor, and pathogenic variants impair complex I assembly and mitochondrial function, contributing to multisystem disease including exercise intolerance, kidney disease and cardiomyopathy. The case highlights the expanding phenotypic spectrum associated with TMEM126B and the importance of periodic gene panel updates and systematic reanalysis to improve diagnostic yield and patient care.
IFT172 is a core component of intraflagellar transport complex B (IFT-B), and pathogenic IFT172 variants disrupt ciliary transport, receptor localization, and tissue-specific signaling. This review summarizes evidence li...IFT172 is a core component of intraflagellar transport complex B (IFT-B), and pathogenic IFT172 variants disrupt ciliary transport, receptor localization, and tissue-specific signaling. This review summarizes evidence linking IFT172 dysfunction to neurological, retinal, skeletal, renal, and syndromic ciliopathy phenotypes, with emphasis on Bardet-Biedl syndrome, Joubert-spectrum disease, orofaciodigital syndrome, Mainzer-Saldino syndrome, and retinal degeneration. Current data support a primary role for IFT172 in IFT-train assembly, tip remodeling, anterograde-to-retrograde transition, and cilia-dependent signaling; downstream metabolic, oxidative, and inflammatory changes are interpreted as context-dependent secondary modules rather than uniform linear cascades. We further discuss diagnostic interpretation and the practical boundaries of gene, splice-correction, and pathway-modulation strategies. By aligning molecular mechanisms with organ vulnerability, this review provides a concise framework for interpreting IFT172-associated ciliopathies and for prioritizing future translational studies.
SEMA6A is a transmembrane protein that plays a role in axon guidance and cell migration. Sema6a null mice have cerebral anatomical defects and altered social interactions and working memory. However, the phenotypes assoc...SEMA6A is a transmembrane protein that plays a role in axon guidance and cell migration. Sema6a null mice have cerebral anatomical defects and altered social interactions and working memory. However, the phenotypes associated with loss of SEMA6A function have not been clearly defined in humans. Here we describe 11 individuals who are heterozygous for putatively damaging variants affecting SEMA6A. All of these individuals (100%) had neurodevelopmental phenotypes that included developmental delay, intellectual disability, and/or autism spectrum disorder. Abnormal behaviors were seen in 73% with oppositional defiant disorder being diagnosed in 27% and acting out, overeating, and tantrums each being described in 18% of individuals. Disorders of attention were documented in 45%. Among the six individuals who had a brain MRI, 50% had at least one abnormal finding. Of the eight SEMA6A variants with known inheritance, five were inherited. Taken together, our data suggest that loss of SEMA6A function may be associated with an increased risk of neurodevelopmental phenotypes, abnormal behaviors, disorders of attention, and brain anomalies. Additional studies will be needed to determine if SEMA6A haploinsufficiency is best characterized as an autosomal dominant disorder with incomplete penetrance or as a risk factor for these phenotypes.
Cousin syndrome (MIM#260660) is a rare genetic disorder characterized by short stature, pelvi-scapular dysplasia and craniofacial dysmorphism, due to biallelic pathogenic variants in the TBX15 gene. So far, only six mole...Cousin syndrome (MIM#260660) is a rare genetic disorder characterized by short stature, pelvi-scapular dysplasia and craniofacial dysmorphism, due to biallelic pathogenic variants in the TBX15 gene. So far, only six molecularly confirmed cases have been reported in the literature. Herein, we report three novel individuals from two unrelated families carrying homozygous novel variants in the TBX15 gene causing Cousin syndrome with detailed phenotypic description. We review the literature and discuss differential diagnoses. This report confirms that Cousin syndrome is a clinically recognizable condition, with typical dysmorphic features, short stature, hypoplastic scapula and iliac wings, a high prevalence of hip dislocation and humero-radial synostosis, transmission deafness and strabismus. More case descriptions are needed to precise the prevalence of intellectual disability in this condition, a feature that seems strikingly variable among reports.
The 2p15p16.1 microdeletion syndrome is a rare neurodevelopmental disorder caused by heterozygous deletions of variable size involving multiple dosage-sensitive genes. Within the narrowed critical interval, USP34 has eme...The 2p15p16.1 microdeletion syndrome is a rare neurodevelopmental disorder caused by heterozygous deletions of variable size involving multiple dosage-sensitive genes. Within the narrowed critical interval, USP34 has emerged as a particularly strong candidate for the core phenotype, supported by reports of smaller deletions involving only USP34 and XPO1, and by the fact that USP34 encodes a deubiquitinating enzyme that stabilizes Axin and thereby regulates canonical Wnt/β-catenin signaling, a pathway critical for neurodevelopment, craniofacial morphogenesis, and limb patterning. We report six individuals with heterozygous loss-of-function variants in USP34, including five with confirmed de novo variants, associated with global developmental delay, craniofacial dysmorphism, marked speech impairment, variable autism spectrum disorder, and distal limb anomalies. The phenotype associated with isolated loss of USP34 overlaps substantially with that reported in 2p15p16.1 microdeletion syndrome, while suggesting that some features seen in larger deletions may reflect the contribution of additional genes within the interval. These findings support haploinsufficiency of USP34 as sufficient to cause a distinct neurodevelopmental disorder, establish USP34 as a major contributor to the neurodevelopmental and dysmorphic phenotype associated with the 2p15p16.1 locus, and refine gene-specific contributions within this microdeletion syndrome.
Growth differentiation factor 2 (GDF2), also known as bone morphogenetic protein-9 (BMP9), is a key member of the transforming growth factor-beta (TGF-β) superfamily, playing a pivotal role in pulmonary vascular regulati...Growth differentiation factor 2 (GDF2), also known as bone morphogenetic protein-9 (BMP9), is a key member of the transforming growth factor-beta (TGF-β) superfamily, playing a pivotal role in pulmonary vascular regulation and remodeling. Dominant variants in GDF2 are known to cause hereditary hemorrhagic telangiectasia type 5 (HHT5), a condition characterized by telangiectases and arteriovenous malformations (AVMs). More recently, recessive variants in GDF2 have been reported to cause pulmonary arterial hypertension (PAH) with or without features of HHT5. In this study, we identified a founder variant in GDF2 that potentially causes semidominant PAH in a cohort of 13 patients ranging in age from pediatric to middle-aged adults. Careful clinical evaluation revealed a wide range of ages of onset and disease severity. However, lack of HHT manifestations was a consistent clinical feature. Our results lend further support to GDF2 as a bona fide disease gene in the context of non-syndromic PAH and demonstrate the power of founder variants to reveal the full spectrum of disease variability.
The WHO Classification of Tumours is used widely by histopathologists and other disciplines as it provides an internationally agreed taxonomy of neoplastic disorders. Now published online and in print, it has often inclu...The WHO Classification of Tumours is used widely by histopathologists and other disciplines as it provides an internationally agreed taxonomy of neoplastic disorders. Now published online and in print, it has often included genetic tumour syndromes (GTS) relevant to particular organs, as suggested by the editorial board. This highlighted the lack of a systematic classification of GTS, providing international standards for their diagnosis and a basis for research. The need for this was established by a series of meetings, leading to the adoption of a hierarchical classification of GTS based on the cellular mechanism affected, the molecular pathway involved, the clinical syndrome and the gene defects present. The major cellular mechanisms affected were identified as: growth factor receptors and related pathways; oxidative stress response and metabolism; cell cycle and apoptosis; DNA repair and genomic stability; telomere maintenance; epigenetic drivers and chromatin; RNA regulation and protein regulation. Assembly of the classification emphasised current gaps in knowledge, together with the need for further research. The new classification highlights the relationships between some genetic syndromes and provides an internationally agreed framework for the incorporation of new information as it becomes available.
CTNNA3 encodes αT-catenin, which contributes to the integrity of the myocardium. Single nucleotide variants are occasionally associated with arrhythmogenic right ventricular cardiomyopathy, and structural variations are...CTNNA3 encodes αT-catenin, which contributes to the integrity of the myocardium. Single nucleotide variants are occasionally associated with arrhythmogenic right ventricular cardiomyopathy, and structural variations are apparently enriched in neurodevelopmental disorders. We report a multiplex family in which a ~60 kb microdeletion of CTNNA3 co-segregates with a variable, heart-restricted phenotype including non-dilated left ventricle cardiomyopathy (NDLVC) in one individual and dilated cardiomyopathy in two, with or without apex hypertrabeculation. The intragenic deletion was identified by XONarray and, subsequently, characterized by long-read sequencing after nonconclusive multigene panel testing. This deletion selectively involved exon 9 and was predicted in-frame by removing 153 amino acids and, thus, disrupting the α-catenin/vinculin-like domain, which is critical for proper conformational homodimerization of the encoded αT-catenin. This intragenic deletion co-segregating with NDLVC and dilated cardiomyopathy confirms that CTNNA3 is a candidate gene for hereditary cardiomyopathies.
RASopathies are clinically and genetically heterogeneous disorders resulting from dysregulation of the RAS/MAPK pathway. We present a single-center retrospective cohort of 118 genotype-confirmed pediatric patients diagno...RASopathies are clinically and genetically heterogeneous disorders resulting from dysregulation of the RAS/MAPK pathway. We present a single-center retrospective cohort of 118 genotype-confirmed pediatric patients diagnosed with RASopathy. Noonan syndrome was the most common clinical diagnosis, followed by NF-Noonan syndrome, Legius syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome. The most frequent clinical features included short stature, pulmonary stenosis, pectus deformities, and neurocognitive delay. Through molecular analysis, we identified distinct variants across major RAS/MAPK pathway genes, with a considerable proportion of patients carrying rare or less frequently reported variants, including those in LZTR1, RIT1, RAF1, HRAS, BRAF, RASA2, KRAS, CBL, SHOC2, and MAP2K2. In addition to well-established genotype-phenotype correlations, we report several uncommon or previously unrecognized features: microcephaly in multiple PTPN11-positive patients and renal agenesis in a child with a novel HRAS variant diagnosed with Costello syndrome. Furthermore, we identified three patients harboring RASA2 variants, providing additional support for its emerging role in Noonan syndrome. This study expands the clinical and molecular spectrum of pediatric RASopathies. It emphasizes the need for comprehensive genetic evaluation and regular follow-up in the context of overlapping clinical features, supporting accurate diagnosis and identifying candidates for emerging targeted therapies.
Bergès C, Sauvestre C, Naudion S
… +28 more, Delorme CV, Smol T, Rama M, Moortgat S, Maystadt I, Kersseboom R, Wilke M, Barakat S, Vial Y, Perrin L, Passemard S, Ahmad F, Umair M, Haack T, Grimmel M, Kuechler A, Slavotinek A, Devine P, Hodoglugil U, Zafar F, Afzal E, Dudding-Byth T, Jouret G, Herissant L, Efthymiou S, Houlden H, Legendre M, Michaud V
Pseudouridylation is a frequent post-transcriptional modification resulting in uridine isomerization in 5-ribosyluracil, also called pseudouridine. This mechanism leads to RNA stability with an increase in base-stacking...Pseudouridylation is a frequent post-transcriptional modification resulting in uridine isomerization in 5-ribosyluracil, also called pseudouridine. This mechanism leads to RNA stability with an increase in base-stacking and the creation of hydrogen bonds. Recently, papers reported that variants in PUS7 in 16 patients were involved in marked growth retardation with microcephaly, associated with intellectual disability and behavioral issues such as self-injurious and aggressive behavior. Through Genematcher, we initiated a collaboration to describe a new cohort of PUS7 patients. In total, we report 13 new cases carrying 15 new variants. This cohort further expands the phenotypic spectrum associated with PUS7-related syndromes, allowing for improved genotype-phenotype correlations and ultimately better healthcare for affected individuals and their families.
Hearing loss (HL) is the most prevalent sensory disorder globally and a major public health challenge in Brazil, affecting over 1.5 million individuals. While over 150 HL-associated genes have been identified, the geneti...Hearing loss (HL) is the most prevalent sensory disorder globally and a major public health challenge in Brazil, affecting over 1.5 million individuals. While over 150 HL-associated genes have been identified, the genetic architecture in underrepresented populations remains poorly defined, often limiting diagnostic yield and precision medicine. We assessed the diagnostic performance of a comprehensive 218-gene HL panel in 99 Brazilian probands (78 non-syndromic; 21 syndromic) who had previously tested negative for GJB2/GJB6 (DFNB1) and MT-RNR1 (m.1555A>G) and did not have ear malformations. Targeted next-generation sequencing was followed by variant interpretation according to ACMG/AMP guidelines, segregation analysis, and longitudinal phenotypic re-evaluation. Integration of Brazil-specific allele-frequency data was used to refine variant classification. A molecular diagnosis or a candidate variant was identified in 61 probands, yielding an overall diagnostic yield of 43%-62%, depending on classification stringency. We identified 19 novel variants across 15 genes, with MYO7A and MYO15A as the most frequently implicated. Notably, 10.4% of patients initially diagnosed with non-syndromic HL carried pathogenic or likely pathogenic variants in syndromic genes (PEX6, BSND, USH1C, and WFS1), necessitating clinical reclassification. Segregation analysis and phenotypic reassessment further enabled the reclassification of three variants of uncertain significance (VUS). In syndromic cases, a molecular diagnosis was established in 41% of cases, including Usher, Waardenburg, Branchio-oto-renal, and Bartter syndromes. This first large-scale clinical genetic evaluation of hearing loss in Brazil demonstrates that comprehensive gene panels incorporating population-specific data significantly improve diagnostic accuracy. Our findings broaden the mutational landscape of HL-associated genes, reinforce the value of integrated genetic approaches for underrepresented populations, and underscore their direct impact on patient care and clinical management.
Pathogenic genetic variants in telomere maintenance genes can lead to accelerated telomere length (TL) shortening. Individuals can pass on significantly shortened TL to their offspring, with or without transmission of th...Pathogenic genetic variants in telomere maintenance genes can lead to accelerated telomere length (TL) shortening. Individuals can pass on significantly shortened TL to their offspring, with or without transmission of the causal genetic variant. Carriers and their progeny are at increased risk for disease in organ systems with high life-time replicative demand, including bone marrow, lungs, and liver. The diagnosis of short telomere related disease is complicated by three factors: the potential for TL inheritance independent of genotype; organ-specific manifestations that evolve across the lifespan; and the lack of a TL cutoff that reliably predicts phenotypic disease. In this manuscript, we suggest that short telomere syndrome (STS) rather than telomere biology disorder (TBD) is the appropriate term for these diseases. We propose a phenotype-based approach to STS that distinguishes among four groups: (1) STS (TL < 10th age adjusted percentile in PBMCs with multiple phenotypic manifestations); (2) short telomeres with one phenotypic manifestation; (3) short telomeres without phenotypic manifestations; and (4) multiple phenotypic manifestations without short telomeres. This approach is intended to guide clinical evaluation of patients with short telomeres and longitudinal risk stratification. We also identify research priorities needed to refine diagnostic thresholds and align TL interpretation with disease biology.
Monoallelic loss-of-function variants of GATA4 have been implicated in congenital heart defects, 46,XY differences of sex development, and congenital diaphragmatic hernia (CDH). However, there is no report of GATA4-varia...Monoallelic loss-of-function variants of GATA4 have been implicated in congenital heart defects, 46,XY differences of sex development, and congenital diaphragmatic hernia (CDH). However, there is no report of GATA4-variant positive patients who concomitantly exhibited these three features. Furthermore, the genotype-phenotype correlation of GATA4 abnormality remains unclear. Here, we report a 2-year-old boy who exhibited pulmonary valve stenosis, multiple atrial septal defects, hypospadias, bifid scrotum, bilateral inguinal hernia, and CDH. Endocrine evaluations of the patient were indicative of partial testicular dysgenesis. Exome sequencing identified a de novo 3-bp deletion in GATA4 that has not been reported previously. The variant eliminated one amino acid from the highly conserved five-threonine repeat in the second zinc finger domain (c.829_831del, p.T277del). The variant was assessed as deleterious by in silico analyses and was scored as "likely pathogenic" by the American College of Medical Genetics and Genomics guidelines. Our findings indicate that the five-threonine repeat in the second zinc finger domain contributes to GATA4 function. These results broaden the spectrum of GATA4 pathogenic variants and highlight the phenotypic diversity resulting from GATA4 abnormalities.