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PubMed2024

Two novel TMEM67 variations in a Chinese family with recurrent pregnancy loss: a case report.

BACKGROUND: Recurrent pregnancy loss (RPL) is a common pregnancy complication that brings great pain to pregnant women and their families. Genetic factors are an important cause reason of RPL. However, clinical research on monogenic diseases with recurrent miscarriage is insufficient. CASE PRESENTATION: Here we reported a Chinese family with RPL and genetic analysis of the abortion and parents. A paternally inherited heterozygous missense variant c.1415T > G (p.V472G) and a maternally inherited heterozygous nonsense variant c.2314del (p.M772*) in TMEM67 gene were identified by trio-exome sequencing. c.2314del (p.M772*) generated a premature stop codon and truncated protein, was classified as "pathogenic". c.1415T > G (p.V472G) located in extra-cellular region, was classified as "likely pathogenic". Biallelic variants in TMEM67 gene cause lethal Meckel syndrome 3, consistent with the proband's prenatal phenotype. CONCLUSION: The current study of the Chinese family expands the pathogenic variant spectrum of TMEM67 and emphasizes the necessity of exome sequencing in RPL condition.

Adult↗

PubMed2025

Antenatal phenotype associated with PAK2 pathogenic variants: bilateral pleural effusion as a warning sign.

Fetal pleural effusions can arise in various contexts with different prognosis. They have been reported in fetuses presenting with hereditary or acquired conditions. One particularly rare genetic disorder, known as Knobloch syndrome, seems to emerge as a potential new cause of fetal pleural effusions, associated with severe outcomes. Knobloch syndrome 1 can be caused by biallelic variants in COL18A1. It is primarily characterized by its ophthalmic features, including severe vitreoretinal degeneration with retinal detachment and macular abnormalities. Neurological defects such as encephalocele and developmental delay, along with skeletal and renal malformations, are also associated with the syndrome. The Knobloch syndrome 2 is caused by monoallelic variants in the kinase domain of PAK2. It is less described and seems to also be associated with cardiac and respiratory damage in addition to the Knobloch syndrome 1 phenotype. PAK2 is a ubiquitous protein with a major implication in regulation and remodeling of the cytoskeleton and numerous other cellular pathways. Knobloch-associated variants seem to cause a loss of the kinase function of the protein. Even if the ophthalmic defects are almost constant, PAK2-associated Knobloch syndrome has slightly different features from Knobloch syndrome 1 in which pulmonary and lymphatic damages are still unseen. In a prenatal trio exome sequencing, we identified a novel de novo PAK2 missense variant, NM_002577.4:c.836 A > C, p.(Gln279Pro), classified as likely pathogenic in a 24 weeks of gestation fetus whose only sign was severe bilateral pleural effusion. From a literature review of patients, we recognize this sign as an important antenatal indicator of Knobloch syndrome 2, as it was the first sign identifiable in 2 out of 5 patients. This adds new evidence for the implication of this gene in fetal pleural effusions, with potentially severe outcomes.

Female↗

PubMed2026

Early-Onset Retinopathy in Patients With Variants in SLC6A6 Leading to Impaired Taurine Transport.

IMPORTANCE: Inherited retinal dystrophies are a group of disorders that may lead to progressive vision loss. Improved knowledge of their molecular genetics is important for accurate diagnosis or development of targeted therapies. OBJECTIVE: To identify pathogenic variants in the SLC6A6 gene (encoding TauT, the main transporter for taurine) and assess their role in the molecular pathogenesis of hereditary early-onset retinal dystrophy (EORD) in affected individuals from diverse ethnic backgrounds. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective, multicenter observational study conducted between June 2019 and March 2025, involving 7 affected and 10 unaffected individuals from 4 unrelated families recruited in Pakistan, Italy, the US, and France. EXPOSURE: Pathogenic variants in SLC6A6 in individuals with EORD. MAIN OUTCOMES AND MEASURES: Genetic, clinical, and functional outcomes of pathogenic variants in SLC6A6 in individuals with Leber congenital amaurosis (LCA) and EORD. All patients underwent standard clinical examinations, including visual acuity, full-field electroretinography, and multimodal retinal imaging, followed by measurement of fasting plasma taurine levels. In vitro and ex vivo taurine transport and membrane trafficking assays in human embryonic kidney (HEK)-293 cells, as well as patient-derived fibroblasts, were also performed. RESULTS: All 7 affected individuals exhibited LCA/EORD, with extraocular findings in some. Genetic analysis identified homozygous pathogenic SLC6A6 variants in all affected individuals, while unaffected relatives were heterozygous carriers. Families 1 and 2 carried missense variants p.(Thr249Ile) and p.(Ala294Thr), while families 3 and 4 carried truncating variants-a deletion of exon 11 and p.(Thr113Ter), respectively. Functional studies demonstrated that both missense variants are associated with complete loss of taurine transport in HEK-293 cells and patient-derived fibroblasts. Additionally, irrespective of the variants considered, plasma taurine levels in affected individuals were reduced compared with heterozygous carriers (difference between means, -31.7 µmol/L; 95% CI, -42.7 to -20.8; P < .001) and healthy control individuals (difference between means, -37.7 µmol/L; 95% CI -41.6 to -33.8; P < .001). CONCLUSIONS AND RELEVANCE: These findings confirm and expand the role of biallelic variants in SLC6A6 in association with LCA/EORD due to impaired taurine transport. These findings suggest that patients with a diagnosis of SLC6A6-related LCA/EORD may be candidates for investigational oral taurine supplementation.

Humans↗

PubMed2025

Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.

Variants in spliceosomal small nuclear RNA (snRNA) genes RNU4-2 (ReNU syndrome), RNU5B-1, and RNU2-2 have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, previously overlooked role for noncoding snRNAs in human disease. Here, we systematically analysed 200 potentially functional snRNA genes in a French cohort comprising 26,911 individuals with rare disorders and through international collaborations. We identify de novo and biallelic variants in RNU2-2 associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive RNU2-2 NDD is at least twice as frequent as the dominant NDD caused by n.4G>A and n.35A>G, and often arises from a de novo variant in trans with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive RNU2-2-NDDs share overlapping clinical features with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our findings support a gradient-of-impact model and a continuum between dominant and recessive inheritance, establishing RNU2-2 variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome.

Journal Article↗

PubMed2024

A novel start-loss mutation of the SLC29A3 gene in a consanguineous family with H syndrome: clinical characteristics, in silico analysis and literature review.

BACKGROUND: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene. METHODS: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing. RESULTS: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein. CONCLUSION: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition.

Humans↗

PubMed2024

Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder.

PURPOSE: The function of FAM177A1 and its relationship to human disease is largely unknown. Recent studies have demonstrated FAM177A1 to be a critical immune-associated gene. One previous case study has linked FAM177A1 to a neurodevelopmental disorder in 4 siblings. METHODS: We identified 5 individuals from 3 unrelated families with biallelic variants in FAM177A1. The physiological function of FAM177A1 was studied in a zebrafish model organism and human cell lines with loss-of-function variants similar to the affected cohort. RESULTS: These individuals share a characteristic phenotype defined by macrocephaly, global developmental delay, intellectual disability, seizures, behavioral abnormalities, hypotonia, and gait disturbance. We show that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA sequencing and metabolomic data sets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation. CONCLUSION: Our data shed light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity.

Humans↗

PubMed2024

Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders.

PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of "ribosomopathies."

Humans↗

PubMed2025

Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency: From metabolism to clinical implications.

PURPOSE: Ketone bodies represent an important energy source and can contribute much to the energy supply of the brain. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency (HMGCS2D) is an autosomal recessive disorder of ketogenesis caused by biallelic variants in HMGCS2. Only 59 patients with this disorder have been reported so far. METHODS: We performed a comprehensive literature search to identify all published cases of HMGCS2D (n = 59). Additionally, the data of 16 patients with this disorder who are yet undescribed were collected. Clinical course, biochemical findings, and mutation data are highlighted and discussed. An overview on all HMGCS2 variants reported in patients is provided. RESULTS: Sixty-eight patients (91%) presented with an acute metabolic decompensation, mostly within the first year of life but beyond the neonatal period. Asymptomatic individuals were identified in several families. Six patients (8%) had died, mainly during the initial metabolic crisis. The neurologic long-term outcome of surviving patients was favorable with almost all patients (98%) showing normal development. Only 1 variant was identified to be common, (HMGCS2) NM_005518.4:c.634G>A p.(Gly212Arg), and found in 6 families. No genotype-phenotype correlation can be established. CONCLUSION: This comprehensive data analysis provides an overview on all published patients reported with HMGCS2D, including a list of HMGCS2 variants identified in affected individuals.

Child↗

PubMed2025

Comprehensive genotypic, phenotypic, and biochemical characterization of GOT2 deficiency: A progressive neurodevelopmental disorder with epilepsy and abnormal movements.

PURPOSE: Glutamic-oxaloacetic transaminase (GOT), also known as aspartate aminotransferase, catalyzes the reversible transamination of oxaloacetate and glutamate to aspartate and α-ketoglutarate. Two isoforms, cytosolic (GOT1) and mitochondrial (GOT2), are integral to the malate-aspartate shuttle, a key regulator of intracellular redox homeostasis. Recently, 5 patients with biallelic variants in GOT2 were described, presenting with developmental and epileptic encephalopathy. METHODS: We report 11 additional patients with homozygous GOT2 variants, along with additional data from 4 previously reported patients. Through genetic, clinical, and biochemical analyses, we further characterize the phenotypic spectrum of GOT2 deficiency. RESULTS: Most patients exhibited progressive neurodevelopmental delay, severe to profound intellectual disability, infantile epilepsy, progressive microcephaly, and hypotonia evolving into spasticity with axial hypotonia. Dysmorphic features included narrow foreheads, broad nasal tips, and tall or pointed chins. Neuroimaging revealed 2 severity groups based on cerebral volume loss and myelination defects. Thinning of the corpus callosum and white matter abnormalities were common. Biochemical profiling identified low aspartate and high glycerol-3-phosphate in dried blood spots as potential screening markers. Patient fibroblast cells showed reduced serine and glycine biosynthesis, rescuable by pyruvate supplementation. CONCLUSION: These findings expand the phenotypic spectrum of GOT2 deficiency, establish it as a cause of developmental epileptic encephalopathy, and propose novel biomarkers for diagnosis and treatment.

Humans↗

PubMed2026

Characterization of a series of patients with GNE-related thrombocytopenia: insights into pathogenesis, diagnosis, and treatment.

BACKGROUND: GNE-related thrombocytopenia (GNE-RT) is a very rare disorder caused by biallelic variants in GNE, which encodes a key enzyme in sialic acid biosynthesis. Patients usually present with severe thrombocytopenia and excessive bleeding. Knowledge of this condition remains limited. There are no recognized diagnostic tests for the diagnosis of GNE-RT. A previous study showed reduced platelet half-life as a mechanism of thrombocytopenia; however, it remains unclear whether the sialylation defect also impairs platelet biogenesis. OBJECTIVES: To gain insights into the clinical aspects and platelet biogenesis of GNE-RT. METHODS: We investigated 4 new GNE-RT patients (3 families). A recently standardized flow cytometry assay was used to characterize platelet sialylation. Patients' megakaryocytes were cultured to study megakaryopoiesis and proplatelet formation. A validated 3-dimensional bone marrow model was used to investigate platelet production. RESULTS: We characterized 3 novel GNE variants and demonstrated the pathogenicity of 2 variants of uncertain significance. In all individuals, platelet flow cytometry showed increased RCA-1 and ECL lectin binding and decreased MAL-II binding. Sialylation of serum transferrin showed no clear alterations. Despite the sialylation defect, patients' megakaryocytes showed preserved differentiation, maturation, and proplatelet formation. Ex vivo, megakaryocytes produced a normal number of normal-sized platelets. Two patients received eltrombopag and achieved a durable clinical response (38- and 72-month follow-up). CONCLUSION: The profound megakaryocyte sialylation defect induced by GNE variants does not affect platelet biogenesis. Platelet flow cytometry assessing RCA-1 and MAL-II binding is a reliable, simple assay for diagnosing GNE-RT. Based on a literature review, 55% of GNE-RT patients respond to thrombopoietin mimetics.

GNE gene↗

PubMed2023

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies.

Discrete categorization of Mendelian disease genes into dominant and recessive models often oversimplifies their underlying genetic architecture. Cardiomyopathies (CMs) are genetic diseases with complex etiologies for which an increasing number of recessive associations have recently been proposed. Here, we comprehensively analyze all published evidence pertaining to biallelic variation associated with CM phenotypes to identify high-confidence recessive genes and explore the spectrum of monoallelic and biallelic variant effects in established recessive and dominant disease genes. We classify 18 genes with robust recessive association with CMs, largely characterized by dilated phenotypes, early disease onset and severe outcomes. Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively. Our data provide insights into the complex spectrum of dominance and recessiveness in genetic heart disease and demonstrate how such approaches enable the discovery of unexplored genetic associations.

Cardiovascular genetics↗

PubMed2024

Delayed diagnosis of mild mucopolysaccharidosis type IVA.

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by biallelic variants in the N-acetylgalactosamine-6-sulfatase (GALNS) gene and is characterized by progressive and multi-system involvements, dominantly with skeletal deformities. A mild form of MPS IVA often presents with atypical symptoms and can go unrecognized for years. METHODS: The diagnosis of MPS IVA was confirmed via GALNS enzyme activity testing in leukocytes. Clinical features were collected. Molecular analysis was performed by next generation sequence and Sanger sequencing of the GALNS gene. The pathogenicity of the deep intron variant was verified by mRNA analyses. RESULTS: Thirteen patients with mild MPS IVA from six families were included. All probands first visit pediatric orthopedists and it took 5.6 years to be diagnosed after the disease onset. The most common symptoms in our series were waddling gait (85%), short neck (69%) and flat feet (62%). Radiologic findings indicated skeletal abnormalities in all patients, especially modification of the vertebral bodies (100%) and acetabular and femoral head dysplasia (100%). Five novel GALNS variants, including c.121-2_121-1insTTTGCTGGCATATGCA, E2 deletion, c.569 A > G, c.898 + 2 T > A, and c.1139 + 2 T > C, were identified. The most common variant, a deep intron variant NM_000512.5: c.121-210 C > T (NM_001323544.2: c.129 C > T, p.G43G), was revealed to result in an 11 bp deletion (c.128_138delGCGATGCTGAG, p.Gly43Aspfs*5) on GALNS mRNA in the GALNS transcript of NM_001323544.2. CONCLUSIONS: This study provides significant insights into the clinical features and molecular characteristics that contribute to the early diagnosis of mild MPS IVA. On the basis of our cohort, orthopedists need to be able to recognize signs and symptoms of mild MPS IVA as well as the molecular and biochemical diagnosis so that an early diagnosis and treatment can be instituted.

Humans↗

PubMed2025

Novel genetic determinants contribute to hearing loss in a central European cohort with enlarged vestibular aqueduct.

BACKGROUND: The enlarged vestibular aqueduct (EVA) is the most commonly detected inner ear malformation. Biallelic pathogenic variants in the SLC26A4 gene, coding for the anion exchanger pendrin, are frequently involved in determining Pendred syndrome and nonsyndromic autosomal recessive hearing loss DFNB4 in EVA patients. In Caucasian cohorts, the genetic determinants of EVA remain unknown in approximately 50% of cases. We have recruited a cohort of 32 Austrian patients with hearing loss and EVA to define the prevalence and type of pathogenic sequence alterations in SLC26A4 and discover novel EVA-associated genes. METHODS: Sanger sequencing, single nucleotide polymorphism (SNP) assays, copy number variation (CNV) testing, and Exome Sequencing (ES) were employed for gene analysis. Cell-based functional and molecular assays were used to discriminate between gene variants with and without impact on protein function. RESULTS: SLC26A4 biallelic variants were detected in 5/32 patients (16%) and monoallelic variants in 5/32 patients (16%). The pathogenicity of the uncharacterized SLC26A4 protein variants was assigned or excluded based on their ion transport function and cellular abundance. The monoallelic or biallelic Caucasian EVA haplotype was detected in 7/32 (22%) patients, but its pathogenicity could not be confirmed. X-linked pathogenic variants in POU3F4 (2/32, 6%) and biallelic pathogenic variants in GJB2 (2/32, 6%) were also found. No CNV of SLC26A4 and STRC genes was detected. ES of eleven undiagnosed patients with bilateral EVA detected rare sequence variants in six EVA-unrelated genes (monoallelic variants in SCD5, REST, EDNRB, TJP2, TMC1, and two variants in CDH23) in five patients (5/11, 45%). Cell-based assays showed that the TJP2 variant leads to a mislocalized protein product forming dimers with the wild-type, supporting autosomal dominant pathogenicity. The genetic causes of hearing loss and EVA remained unidentified in (14/32) 44% of patients. CONCLUSIONS: The present investigation confirms the role of SLC26A4 in determining hearing loss with EVA, identifies novel genes in this pathophysiological context, highlights the importance of functional testing to exclude or assign pathogenicity of a given gene variant, proposes a possible diagnostic workflow, suggests a novel pathomechanism of disease for TJP2, and highlights voids of knowledge that deserve further investigation.

Humans↗

PubMed2025

Recessive FANCM cancer syndrome with high cancer risks, chemotherapy toxicity, chromosome fragility, and gonadal failure.

PURPOSE: Heterozygous FANCM variants have been associated with breast cancer. Only a few studies have examined other cancer types. Biallelic truncating variants have been linked to a Fanconi anemia (FA)-like cancer prone syndrome in case reports; however, the range of cancers and the risk estimates are lacking. METHODS: We studied the association of Finnish-enriched variants c.5101C>T p.(Gln1701Ter) and c.5791C>T p.(Arg1931Ter) with risk of any cancer and FA-related conditions in the FinnGen data with 500,348 individuals. RESULTS: Heterozygous c.5101C>T (N = 10,940) was associated not only with an increased risk of breast cancer (odds ratio = 1.24, P = 2.7 × 10-6) but also with risks of other cancer types, including hypopharyngeal (odds ratio = 3.98, P = 3.6 × 10-7), suggesting a risk effect wider than previously described. Homozygous c.5101C>T (N = 76) was associated with a high risk of breast, head and neck, gastrointestinal, gynecological, hematologic, skin, and lung cancer, whereas c.5791C>T was rare. Additionally, high recessive risks of ovarian dysfunction and hematologic side effects after cancer treatment were detected, but no risks of bone marrow failure or physical features of FA. CONCLUSION: Based on the pattern of risks associated with biallelic variants, we suggest a novel FANCM cancer syndrome that is separate from FA and other characterized cancer susceptibility syndromes.

Humans↗

PubMed2026

Biallelic EZH1 Nonsense Novel Variant in Two Siblings with Neurodevelopmental Disorder and Central Precocious Puberty: A Case Report from a Consanguineous Saudi Family.

Neurodevelopmental disorders (NDDs) are a group of conditions that impair the development and function of the central nervous system. Recently, variants in the EZH1 gene have been associated with neurodevelopmental disorders. Here, using whole-exome sequencing coupled with confirmatory Sanger sequencing, we identified a homozygous nonsense variant in EZH1 in two affected siblings. Both parents were heterozygous carriers of the variant. The variant is predicted to result in a 44-amino acid C-terminal truncation within the catalytic SET domain, leading to loss of protein function. RT-qPCR analysis revealed significantly reduced EZH1 mRNA expression in patient-derived peripheral blood cells. The index patient (female) also exhibited elevated gamma-glutamyl transferase (GGT) levels and hypoalbuminemia, whereas the affected male presented with central precocious puberty. This study further expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism.

Child↗

PubMed2026

The Same Homozygous Pathogenic Variant in CHAT Underlies Lethal Fetal Akinesia Syndrome in Three Xhosa South African Fetuses.

What is already known about this topic? ◦. Biallelic pathogenic variants in CHAT cause congenital myasthenic syndrome (CMS), typically presenting postnatally with episodic apnea and neuromuscular weakness. CHAT encodes choline acetyltransferase, essential for acetylcholine synthesis at the neuromuscular junction, and previously has not been associated with uniformly lethal prenatal phenotypes. What does this study add? ◦. We demonstrate that biallelic CHAT variants can cause severe fetal akinesia resulting in lethal multiple pterygium syndrome, expanding the phenotypic spectrum to include presentation, lethality and supporting inclusion of CHAT in fetal akinesia gene panels.

CHAT↗

PubMed2026

Biallelic ABCA13 Loss-of-Function Variants in a Child With Neurodevelopmental Delay: A Case Report.

ABCA13 encodes ATP-binding cassette subfamily A member 13, one of the largest members of the ABC transporter family. Rare ABCA13 variants have been reported in neuropsychiatric and neurodevelopmental phenotypes, including schizophrenia, bipolar disorder, autism spectrum disorder, intellectual disability, and developmental delay; however, the mode of inheritance remains uncertain, and most published cases have focused on heterozygous variants in the context of a possible dominant or susceptibility model. We report a 5-year-old boy with neurodevelopmental delay, skeletal foot deformities, nonspecific dysmorphic features, convergent strabismus, and behavioral abnormalities. Initial genome sequencing analysis was nondiagnostic. Reanalysis after 6 months identified two rare predicted loss-of-function variants in ABCA13 in trans: c.2510del, p.(Leu837TyrfsTer21), a frameshift variant, and c.12064C>T, p.(Arg4022Ter), a nonsense variant previously reported in a patient with unexplained intellectual disability. The identification of compound heterozygous predicted loss-of-function variants supports the possibility that biallelic disruption of ABCA13 may contribute to neurodevelopmental disease, whereas previously reported heterozygous variants may represent incompletely penetrant risk alleles, susceptibility factors, or candidate findings rather than fully penetrant dominant causes. This case expands the emerging clinical and genetic spectrum associated with ABCA13 and supports further evaluation of a recessive model in patients with intellectual disability and neurodevelopmental delay.

ABCA13↗

PubMed2024

Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.

PURPOSE: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single-case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations. METHODS: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies. RESULTS: We characterize a clinically variable disorder with cardinal features, including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a-/- mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition. CONCLUSION: Our studies comprehensively characterize INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose that the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.

Humans↗