Singerline H, Laufman J, Wallis K
… +1 more, Merrill M
Am J Med Genet A
· 2026 Jun · PMID 41540951
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Homozygous achondroplasia is widely considered perinatal lethal by the medical community. In this case series, we report two children from a single family with longer-term survival. One child lived for 17 months and the...Homozygous achondroplasia is widely considered perinatal lethal by the medical community. In this case series, we report two children from a single family with longer-term survival. One child lived for 17 months and the other was 60 months at the time of publication. We describe two siblings born to parents with achondroplasia with homozygous achondroplasia and long-term survival.
Rabin R, Booth KTA, Cowper SE
… +5 more, Choate K, Rubin BY, Ekstein J, Pappas J, Hirsch Y
Am J Med Genet A
· 2026 May · PMID 41531333
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Trichothiodystrophies (TTDs) are a group of disorders that have been characterized by sparse, brittle, and sulfur deficient hair that showed a "tiger-tail" banding pattern. Though the majority of TTDs are inherited in an...Trichothiodystrophies (TTDs) are a group of disorders that have been characterized by sparse, brittle, and sulfur deficient hair that showed a "tiger-tail" banding pattern. Though the majority of TTDs are inherited in an autosomal recessive pattern, RNF113A related trichothiodystrophy is X-linked. RNF113A-related TTD has been associated with a non-photosensitive trichothiodystrophy, characterized by intellectual disability, microcephaly, growth restriction and failure, genital abnormalities, endocrine abnormalities, recurrent infections, and abnormal brain magnetic resonance imaging (MRI). To date, six individuals have been described with RNF113A-related TTD. Here we describe two brothers in their 30's with a novel hemizygous variant c.635G>A p.Gly212Asp in the RNF113A gene, which is not present in the tissues tested in their mother. Protein modeling suggests significant structural alteration. The brothers are the oldest known affected individuals and have features consistent with X-linked trichothiodystrophy including intellectual disability, microcephaly, growth failure, dysmorphic features, severe myopia and tiger-tail banding pattern. Absence of endocrinological abnormalities, recurrent infections, genital abnormalities, and abnormal MRI showed that these are not universal findings of RNF113A related trichothiodystrophy. Given that absence of the variant in the patients' mother, we presume the mother to have low level somatic mosaicism or germline mosaicism for the variant. This highlights the importance of genetic counseling for accurate recurrence risks and warranted reproductive testing for parents and female siblings of affected individuals with presumed de novo variants.
Gündoğdu Öğütlü OB, Demir B, Utlu Z
… +3 more, Karabak M, Keskin F, Yaralı O
Am J Med Genet A
· 2026 May · PMID 41531171
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Pathogenic variants in NCKAP1, a gene encoding a core component of the WAVE regulatory complex (WRC), have recently been implicated in neurodevelopmental disorders (NDDs), but the clinical spectrum remains incompletely c...Pathogenic variants in NCKAP1, a gene encoding a core component of the WAVE regulatory complex (WRC), have recently been implicated in neurodevelopmental disorders (NDDs), but the clinical spectrum remains incompletely characterized. We describe a father and daughter carrying a novel heterozygous NCKAP1 splice-site variant (c.2021+1G>A), both presenting with developmental delay, autistic features, epilepsy, and shared craniofacial dysmorphisms. Although familial cases have been previously reported, this is the first to present thorough phenotypic documentation, including longitudinal neurodevelopmental and neuroimaging follow-up, dermatologic involvement, and dysmorphic evaluation in both the parent and the child. Notably, both individuals showed nail dystrophy and inflammatory skin lesions, expanding the phenotypic range of NCKAP1-related disorders beyond the nervous system. Comparative analysis revealed significant overlap with reported features of RAC1, CYFIP2, and WASF1-related syndromes, genes that also encode components of the WRC, further supporting a shared pathophysiological mechanism involving cytoskeletal dysregulation. Expression data from GTEx and HPA confirm that NCKAP1 is not only neuronally expressed but also found in epithelial tissues, providing biological plausibility for the dermatologic manifestations. This report contributes new clinical insights into NCKAP1-associated NDDs and emphasizes the importance of detailed phenotyping in rare familial cases to refine gene-disease associations.
Gupta S, Kanago D, Tilak P
… +11 more, Reddy BS, Indla G, Gowda M, Asegaonkar P, Sharda S, Arora V, Purohit P, Yadav KM, Shah N, Shah P, Kotecha U
Am J Med Genet A
· 2026 May · PMID 41521578
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The prognosis in Binder phenotype is influenced by underlying etiology and associated findings. Genetic testing till date has focused on chromosomal anomalies and targeted testing of genes like ARSL (previously ARSE). Th...The prognosis in Binder phenotype is influenced by underlying etiology and associated findings. Genetic testing till date has focused on chromosomal anomalies and targeted testing of genes like ARSL (previously ARSE). The aim of this study was to assess the utility of exome sequencing in fetuses with antenatal Binder phenotype and explore how its results influence parental reproductive decision-making. This retrospective study included 50 fetuses with sonographic features of Binder phenotype who underwent exome sequencing with copy number variant calling. Semi-structured follow-up interviews were conducted with families to understand the rationale behind reproductive decisions. Pathogenic or likely pathogenic variants were detected in four cases, while phenotypically relevant variants of uncertain significance were observed in six additional cases. Notably, variants in GNPTAB, a novel association, were identified in two unrelated cases. Of the 31 families who awaited test results, 20 continued the pregnancy, while 7 chose termination despite negative or uncertain findings. Overall, 55% of pregnancies were electively terminated, driven by variant findings, ultrasound severity, recurrence, or previous outcomes. Genetic testing provided meaningful insights in select cases, but reproductive decisions were influenced by a broader range of clinical and psychosocial factors. We conclude that exome sequencing can support but does not dictate prenatal decision-making.
Am J Med Genet A
· 2026 May · PMID 41518091
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DEAF1-associated neurodevelopmental disorder (DAND) is a neurodevelopmental spectrum disorder caused by two methods of inheritance: the autosomal dominant intellectual disability syndrome (Vulto-van Silfout-de Vries synd...DEAF1-associated neurodevelopmental disorder (DAND) is a neurodevelopmental spectrum disorder caused by two methods of inheritance: the autosomal dominant intellectual disability syndrome (Vulto-van Silfout-de Vries syndrome (VSVS), OMIM #615828), and the autosomal recessive Neurodevelopmental disorder with hypotonia and impaired expressive language with or without seizures (NEDHELS OMIM #615828) (OMIM 617171). All reported cases of VSVS have occurred de novo. In this report, we describe the case of a 2-year-old male with a history of autism spectrum disorder and behavioral concerns who was identified to be heterozygous for the c.837C>G (p.C279W) pathogenic variant in DEAF1. Functional assays demonstrate that the p.C279W variant alters DEAF1's transcriptional repression activity. This variant was also identified in his 26-year-old mother, who also has a history of autism and speech delay. To the best of our knowledge, this is the first reported case of the dominant form of DEAF1-associated neurodevelopmental disorder inherited from an affected parent.
Acikgoz NB, Demir GU, Yildiz Y
… +8 more, Duz MB, Sener N, Alpat S, Kesici S, Ertugrul I, Yalnizoglu D, Utine GE, Kiper POS
Am J Med Genet A
· 2026 May · PMID 41508548
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We report two siblings harboring a homozygous MGME1 variant, NM_052865.4:c.818 T>A; p.(Val273Glu), both presenting with ptosis, myopathy, scoliosis, and gastrointestinal symptoms. The index patient developed progressive,...We report two siblings harboring a homozygous MGME1 variant, NM_052865.4:c.818 T>A; p.(Val273Glu), both presenting with ptosis, myopathy, scoliosis, and gastrointestinal symptoms. The index patient developed progressive, medically refractory dilated cardiomyopathy and underwent successful orthotopic heart transplantation (OHT). Reanalysis of previously negative WES identified the variant in the index case, and segregation by Sanger sequencing confirmed homozygosity in both siblings. Although several clinical findings overlap with previously described MGME1-related disease, the detected variant remains classified as a variant of uncertain significance (VUS); thus, functional evidence is needed to better understand its potential causal relevance. Additionally, this report underscores the importance of periodic genomic data reanalysis and highlights the variable expressivity that may occur even within the same family.
Madenidou AV, Rice GI, O'Sullivan J
… +4 more, Parker B, Bruce IN, Burkitt-Wright E, Briggs TA
Am J Med Genet A
· 2026 May · PMID 41496732
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RASopathies are clinically overlapping neurodevelopmental syndromes resulting from germline mutations in genes involved in the rat sarcoma/mitogen-activated protein kinases (RAS/MAPK) pathway. Historically, RASopathies h...RASopathies are clinically overlapping neurodevelopmental syndromes resulting from germline mutations in genes involved in the rat sarcoma/mitogen-activated protein kinases (RAS/MAPK) pathway. Historically, RASopathies have been described by clinical phenotypes, such as Noonan syndrome and Neurofibromatosis type I. There is emerging evidence of the association between Noonan syndrome spectrum disorders (NSSD) and systemic lupus erythematosus (SLE). Here, we present an SLE patient diagnosed with SOS1-associated Noonan Syndrome (c.806 T>C; p.Met269Thr) as part of a research study. Reviewing the literature, we identified further 16 cases of NSSD associated with SLE. Nine out of 16 cases (56%) had a confirmed molecular diagnosis, with pathogenic missense variants identified in KRAS, PTPN11, and SHOC2 genes, the majority in the last. Variants in SHOC2 are the cause of only a small proportion of all presentations of NSSD. Our case represents the first reported case of SLE in a patient with a SOS1 pathogenic variant. Compared to the general SLE population, SLE in the presence of NSSD develops at a younger age, with a similar prevalence among females and males, suggesting a contribution of the RAS/MAPK pathway in the development of SLE.
Am J Med Genet A
· 2026 May · PMID 41493289
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Missense variants in the KCNQ2 gene can cause developmental and epileptic encephalopathy (DEE). While most KCNQ2-DEE cases are attributed to loss-of-function (LOF) mutations, gain-of-function (GOF) mutations have also be...Missense variants in the KCNQ2 gene can cause developmental and epileptic encephalopathy (DEE). While most KCNQ2-DEE cases are attributed to loss-of-function (LOF) mutations, gain-of-function (GOF) mutations have also been implicated in the disorder. This study describes the clinical features of a DEE patient with a KCNQ2 mutation in the voltage-sensing domain (VSD) and analyzes the variant's electrophysiological properties. Whole-exome sequencing was performed to identify the genetic variant. Whole-cell patch-clamp electrophysiology was used to characterize the functional effects of the mutant channel, both alone and in combination with KCNQ3 subunits at a 1:1:2 ratio to mimic the patient's allele dosage. The effect of amitriptyline (AMI) on channel activity was also evaluated. A three-year-old female with early-onset epileptic encephalopathy presented with intractable seizures, developmental regression, microcephaly, transient thyroid dysfunction, and a mixed EEG pattern of hypsarrhythmia and intermittent burst-suppression. A de novo KCNQ2 variant (c.401T>A, p.Ile134Asn) located in the conserved S2 transmembrane domain was identified and classified as likely pathogenic. Electrophysiological analysis showed that the KCNQ2-I134N mutation caused a hyperpolarizing shift in voltage-dependent activation and significantly increased current density, indicating a GOF effect. This GOF phenotype persisted when the mutant subunit was co-expressed with KCNQ3 and under a transfection ratio mimicking the patient's genotype. The hyperactivity of the mutant channel was effectively suppressed by amitriptyline. We report a novel GOF variant (I134N) in the KCNQ2 gene associated with DEE. The KCNQ blocker amitriptyline effectively suppressed mutant channel hyperactivity, suggesting its potential as a targeted therapeutic option for patients with this pathogenic variant.
Yilmaz B, Akoglu G, Sayin S
… +3 more, Kuzu I, Kivrak H, Ayli M
Am J Med Genet A
· 2026 May · PMID 41489023
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Erdheim-Chester disease (ECD) is a rare, systemic, and potentially malignant non-Langerhans cell histiocytosis characterized by the infiltration of foamy histiocytes into multiple organ systems. The diagnosis of ECD is o...Erdheim-Chester disease (ECD) is a rare, systemic, and potentially malignant non-Langerhans cell histiocytosis characterized by the infiltration of foamy histiocytes into multiple organ systems. The diagnosis of ECD is often complicated and time-consuming due to its rarity and heterogeneous presentation. A 39-year-old female presented with a progressively enlarging yellowish plaque measuring 5 × 2 cm on left periorbital skin over the past 2 years. Besides, the patient had bilateral lower extremity pain persisting for 1.5 years, significantly affecting her mobility and quality of life. Histological examination of skin biopsies revealed frequent Touton giant cells, bland-appearing histiocytes characterized by abundant foamy (xanthomatous) cytoplasm in the dermis, which were positive for CD68, Factor XIIIa, and BRAF; negative for CD1a and S100. In bone marrow biopsy, histiocytic cells were positively stained with CD68, Factor XIIIa, and CD14, and negatively stained for CD1a, Langerin, and S100. Positron emission tomography/computed tomography imaging revealed pathological 18-fluoro-2-deoxyglucose uptake in the bone marrow and widespread sclerotic bone lesions on the bilateral lower extremity. BRAF sequencing determined a BRAFV600E mutation. The patient was diagnosed with ECD, and vemurafenib was initiated. After 6 months of treatment, significant improvements were observed in both bone pain and the size and discoloration of the yellowish plaque. In conclusion, our case highlights that the primary diagnostic clue for ECD may be a single yellowish plaque, which requires further investigation in relation to other systemic symptoms. Vemurafenib treatment may lead to regression of systemic symptoms and cutaneous yellowish plaques associated with ECD carrying a BRAF mutation.
Ambrosetti I, Cristalli CP, Montanari F
… +12 more, Caramanna L, Modestino F, Capelli I, Aiello V, Lerario S, Evangelisti C, Neri I, Brunocilla E, Rossi C, Seri M, Turchetti D, Innella G
Am J Med Genet A
· 2026 Apr · PMID 41486106
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Mosaicism is relatively common in Tuberous Sclerosis Complex (TSC) but can be difficult to detect using routine diagnostic tests, particularly when the variant allele frequency (VAF) is low. We describe two cases of mosa...Mosaicism is relatively common in Tuberous Sclerosis Complex (TSC) but can be difficult to detect using routine diagnostic tests, particularly when the variant allele frequency (VAF) is low. We describe two cases of mosaic TSC diagnosed using an ultra-deep sequencing approach in multiple tissues and review the literature about this topic in order to discuss new diagnostic paradigms. In the first case, further testing was prompted by the presence of angiomyolipomas in the otherwise unaffected 51-year-old father of a woman diagnosed with TSC2; the familial pathogenic variant was present with a very low VAF in angiomyolipoma tissue and peripheral blood. The second case, a 17-year-old boy diagnosed with infantile myofibromatosis, presented dermatological and brain MRI findings suggestive of TSC; a TSC1 pathogenic variant was first identified on DNA extracted from angiofibroma biopsy, and then confirmed on non-lesional skin, peripheral blood, and saliva. The identification of the causative TSC1/2 variant is crucial to provide appropriate management and genetic counseling for family planning. Most mosaic individuals in the literature have cutaneous features of TSC; in the presence of an accessible lesion, we recommend considering a tissue biopsy to have a higher chance of identifying a low-level mosaicism.
Khan A, Kakar N, Kakar A
… +2 more, Spielmann M, Malik S
Am J Med Genet A
· 2026 May · PMID 41486098
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Marfan syndrome (MFS) is a rare connective tissue disorder characterized by involvement of the cardiovascular, ocular, and musculoskeletal systems. Pathogenic variants in FBN1 cause most of the MFS cases; however, intell...Marfan syndrome (MFS) is a rare connective tissue disorder characterized by involvement of the cardiovascular, ocular, and musculoskeletal systems. Pathogenic variants in FBN1 cause most of the MFS cases; however, intellectual disability (ID) is rarely observed. A non-consanguineous Pakistani family with four affected individuals was recruited. Physical examinations, echocardiography, and doppler ultrasound were performed as part of the clinical assessment. Exome sequencing was conducted on the index patient, and Sanger sequencing was performed for the entire family. ID was the primary symptom in all the affected individuals. A detailed examination showed that all affected individuals and their affected mother were tall, had long limbs, craniofacial abnormalities, and exhibited low IQ, aggressive, and hyperactive behaviors. Heart defects, such as atrial septal defects and pulmonary hypertension, were observed in one affected individual and her mother. Genetic analysis identified two rare missense variants in FBN1, c.1552G>A (p.Gly518Arg) and c.3046A>G (p.Thr1016Ala), both predicted to be deleterious. The p.Gly518Arg variant is predicted to be likely pathogenic, while the p.Thr1016Ala variant is of uncertain significance. Notably, these variants were found in two affected individuals in a compound heterozygous state, correlating with more severe symptoms. Each variant alone, seen in the two patients, is associated with milder symptoms, indicating incomplete penetrance. In conclusion, this study identified rare heterozygous missense variants in FBN1, suggesting a potential connection between neurodevelopmental outcomes and variants in FBN1. However, further research is needed to clarify the role of FBN1 in ID.
AlHashem A, AlQudairy H, Raed J
… +7 more, Al Bulushi B, Faqeih E, Alotbi R, Al Mutairi F, Alfadhel M, Alkuraya F, Kaya N
Am J Med Genet A
· 2026 Apr · PMID 41474134
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Hereditary sensory and autonomic neuropathy type IV (HSAN4) is a rare neurological disorder characterized by anhidrosis and congenital insensitivity to pain caused by biallelic pathogenic variants in NTRK1. The condition...Hereditary sensory and autonomic neuropathy type IV (HSAN4) is a rare neurological disorder characterized by anhidrosis and congenital insensitivity to pain caused by biallelic pathogenic variants in NTRK1. The condition develops because of dorsal root and autonomic ganglion neurodegeneration, which ultimately results in reduced sensation and autonomic neurological dysfunction. We ascertained several neuropathic patients and performed genetic testing using gene panels and exome sequencing (ES). Genetic variants were confirmed by Sanger sequencing. Thirteen families, each with a single affected individual, participated in this study. Genetic testing revealed that all patients carried disease-causing variants in NTRK1. We identified seven different variants within our cohort, including two novel variants (c.1922T>C:p.Leu641Pro and c.1071_1072insTGCC:p.Asn358Cysfs*45). While some variants suggest a possible founder effect, the identification of new variants reflects the genetic diversity within the Saudi population. In addition to the cardinal clinical feature of HSAN4, patients exhibited various other symptoms like motor difficulties, microcephaly, recurrent hip dislocation, dystrophic nails, hypotrichosis, and various dysmorphic features. This study provides clinical information on a large number of patients, updates the prevalence and epidemiologic data in our population, and further expands the understanding of the disease's genetic and clinical spectrum within a highly consanguineous population.
Am J Med Genet A
· 2026 May · PMID 41466375
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Variations in Sex Characteristics (VSC), also referred to as intersex traits or Differences of Sex Development (DSD), encompass diverse chromosomal, gonadal, and anatomical sex traits. The full spectrum of VSC remains un...Variations in Sex Characteristics (VSC), also referred to as intersex traits or Differences of Sex Development (DSD), encompass diverse chromosomal, gonadal, and anatomical sex traits. The full spectrum of VSC remains under-recognized, partly due to diagnostic approaches that prioritize classic VSC/DSD conditions. We developed a 103-term Focused Genitourinary VSC Glossary (FGV Glossary) using Human Phenotype Ontology (HPO) terms and screened 8359 Online Mendelian Inheritance in Man (OMIM) entries for inclusion. Associated genes were evaluated for coverage in clinical DSD panels and assessed in ClinVar for pathogenic variants linked to VSC/DSD phenotypes. We identified 539 OMIM entries (~6.4%) with at least one FGV Glossary term. These entries were enriched for genitourinary, breast, and endocrine phenotypes. Of 56 high-confidence VSC/DSD genes identified, 23 (41%) were absent from a current representative DSD gene panel. A curated ClinVar review showed that 3 of these 23 genes (DHX37, SPRY4, TBX3) had pathogenic variants clearly associated with VSC/DSD traits. Genome-wide sequencing should be prioritized in VSC/DSD diagnostics, consistent with current best practices, to improve diagnostic yield and guide comprehensive, multidisciplinary clinical care.
Gomes A, Martín-Rodríguez Á, Del Campo M
… +1 more, Bird LM
Am J Med Genet A
· 2026 May · PMID 41457890
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The KDM2B-related neurodevelopmental disorder is a recently identified Mendelian disorder of the epigenetic machinery associated with pathogenic variants in KDM2B. Global developmental delay, intellectual disability, con...The KDM2B-related neurodevelopmental disorder is a recently identified Mendelian disorder of the epigenetic machinery associated with pathogenic variants in KDM2B. Global developmental delay, intellectual disability, congenital anomalies, and systemic manifestations characterize the disorder. Variants in KDM2B that primarily affect the CxxC DNA-binding domain are strongly linked to a specific epigenetic signature. We present three children with KDM2B-related neurodevelopmental disorder, each with a heterozygous variant in the CxxC domain of KDM2B. Patient 1 is a 2-year-old boy with developmental delay, solitary kidney, atrial septal defect, feeding difficulties, hemangiomas, and myopic astigmatism. Patient 2 is a 2-year-old girl with global developmental delay, hip dysplasia, feeding difficulties, hemangiomas, and myopic astigmatism. Patient 3 is a 5-year-old girl with autism, developmental delay, atrial septal defect, and ventricular septal defect, hypertrichosis, atopic dermatitis, and myopic astigmatism. Genetic analysis revealed a variant in KDM2B in each patient. Targeted methylation analysis for the epigenetic signature associated with the KDM2B-related syndrome revealed an abnormal methylation pattern consistent with a positive epigenetic signature of the disorder in individuals 2 and 3. These results provided supportive functional evidence for KDM2B-related neurodevelopmental disorder in the context of the clinical findings and KDM2B variants. Our findings emphasize the value of integrating genomic and epigenomic analyses for variant interpretation. This case series reinforces the consistent phenotype of KDM2B-related neurodevelopmental disorder and highlights ocular and dermatologic manifestations as recurring features in affected individuals.
Fatehi F, Ghorbanoghli Z, Kooshki M
… +7 more, Najafabadi SZ, Noudehi K, Amooian S, Taghiloo A, Makvand M, Najmabadi H, Kariminejad A
Am J Med Genet A
· 2026 May · PMID 41449824
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We report a biallelic likely pathogenic variant in the NRDC gene in two Iranian siblings with developmental delay, microcephaly, hypotonia, seizures, and absent speech. Exome sequencing (ES) identified a frameshift delet...We report a biallelic likely pathogenic variant in the NRDC gene in two Iranian siblings with developmental delay, microcephaly, hypotonia, seizures, and absent speech. Exome sequencing (ES) identified a frameshift deletion in exon 15 of NRDC (NM_001101662.2): c.1702_1703del (p.Met568Valfs*2), confirmed to segregate with disease in the family. This is the second report implicating biallelic NRDC gene variants in neurodevelopmental disorders. Our findings expand the phenotypic spectrum and support a potential role for NRDC in severe neurodevelopmental delay.
Am J Med Genet A
· 2026 May · PMID 41436359
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Pathogenic variants in TAMM41 were recently linked to mitochondrial myopathy, presenting with neonatal hypotonia, generalized weakness, developmental delay, ptosis, and ophthalmoparesis. Here, we present a long-term foll...Pathogenic variants in TAMM41 were recently linked to mitochondrial myopathy, presenting with neonatal hypotonia, generalized weakness, developmental delay, ptosis, and ophthalmoparesis. Here, we present a long-term follow-up of an additional case, a Brazilian patient harboring a novel TAMM41 variant in compound heterozygosity with a previously described pathogenic variant. Patient exhibited mild developmental delay, acquired independent gait, but subsequently developed motor regression and weakness associated with recurrent infections, severe axial involvement, and marked restrictive pulmonary dysfunction. Muscle biopsy revealed decreased COX and SDH staining, which may serve as an important diagnostic clue for this condition. This case expanded the genetic spectrum of TAMM41-related mitochondrial myopathy and provided a brief review of disorders associated with reduced SDH staining.
Tark JY, Renwick A, Tettamanti G
… +13 more, Harris RD, Desrosiers TA, Olshan AF, Janitz AE, Scheurer ME, Shumate CJ, Scheuerle AE, Plon SE, Huff CD, Nordgren A, Luke B, Lupo PJ, Schraw JM
Am J Med Genet A
· 2026 May · PMID 41432111
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Cancer risk in children with VACTERL, a nonrandom co-occurrence of ≥ 3 defects (vertebral, anal, cardiac, tracheoesophogeal fistula, renal, and limb), remains unclear. We evaluated this association in a population-based...Cancer risk in children with VACTERL, a nonrandom co-occurrence of ≥ 3 defects (vertebral, anal, cardiac, tracheoesophogeal fistula, renal, and limb), remains unclear. We evaluated this association in a population-based study. We analyzed data from the Genetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Study, a US registry linkage cohort. VACTERL was defined as the presence of ≥ 3 associated defects. Cox regression was applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer risk before age 18 in children with VACTERL compared to children without birth defects. Kaplan-Meier analyses were used to estimate cumulative incidence of cancer in each group. Of 21,224,742 births, 2288 met VACTERL criteria; 8 developed cancer, 5 (63%) of whom were diagnosed with embryonal tumors. Children with VACTERL had a significantly increased cancer risk (HR = 3.0, 95% CI: 1.5-6.0), particularly for embryonal tumors (HR = 6.9, 95% CI: 2.9-16.5), relative to unaffected children. Cancer incidence was 421.3 (95% CI: 181.9, 830.0) per million person-years for VACTERL versus 133.4 (95% CI: 131.8-135.0) for unaffected children. Children with VACTERL may face increased cancer risk. Shared developmental or epigenetic mechanisms may underlie both conditions, highlighting efforts to identify subgroups that may benefit from targeted surveillance.