Costa MP, Ferreira AR, Rodrigues AT
… +21 more, Arantes RR, Queiroz TCN, de Carvalho E, Porta G, Miura IK, Guiotti MTG, Monterlei RKS, de Tommaso AMA, Hessel G, Bellomo-Brandão MÂ, de Alcantara RV, de Araujo MJRT, Meneses DG, Sawamura R, Marques CDF, Alvarenga LR, Tofoli MHC, de Melo ACV, de Cerqueira Maia JM, Lopes LHC, Fagundes EDT
Am J Med Genet A
· 2026 Jul · PMID 41797620
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To describe clinical and laboratory characteristics, emphasizing the evolution of patients with hepatic glycogen storage diseases (GSDs) followed in Brazilian reference centers. Multicenter, retrospective study involving...To describe clinical and laboratory characteristics, emphasizing the evolution of patients with hepatic glycogen storage diseases (GSDs) followed in Brazilian reference centers. Multicenter, retrospective study involving 13 centers, using RedCap platform. 132 patients were included: 63 (47.8%) GSD type I (56 Ia, 7 Ib), 13 (9.8%) with type III (12 IIIa, 1 IIIb), 1 (0.8%) type IV, 6 (4.5%) type VI, and 49 (37.1%) with type IX (28 IXa, 7 IXb, and 14 IXc). Type I patients presented earlier (4 months) and had more episodes of hypoglycemia at clinical presentation (p < 0.001). Anthropometric data at admission revealed impaired growth, with a tendency toward short stature across the groups (median -2.06, -1.89, and -1.96 among type I, III, and IX respectively). The median body mass index (BMI) z-scores at admission for all three types were above +1. Only patients with type IX demonstrated significant improvement in height (p = 0.007) and BMI (p = 0.020) z-scores during follow-up. Regarding laboratory tests, significant decreases were observed in total cholesterol, triglycerides, venous lactate and aminotransferases in patients with types I and IX. Hepatic GSDs are heterogeneous diseases. There is a significant height impairment with a troublesome trend to overweight and obesity, especially in type I. Although there is improvement in aminotransferases, cholesterol, and triglycerides with follow-up, adherence to treatment remains a challenge.
Mathavan A, Mathavan A, Krekora U
… +7 more, Rojas ORG, Huynh K, Lin M, Dinh J, Zumberg MS, Justice J, Ataya A
Am J Med Genet A
· 2026 Jul · PMID 41795626
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Pulmonary arteriovenous malformations (PAVMs) are rare vascular anomalies most commonly seen in hereditary hemorrhagic telangiectasia (HHT), a condition associated with mutations in ENG, ACVRL1, SMAD4, or GDF2. In contra...Pulmonary arteriovenous malformations (PAVMs) are rare vascular anomalies most commonly seen in hereditary hemorrhagic telangiectasia (HHT), a condition associated with mutations in ENG, ACVRL1, SMAD4, or GDF2. In contrast, BMPR2 variants are well-established in heritable pulmonary arterial hypertension (PAH), but their relationship to PAVMs remains poorly understood. We report the case of a 41-year-old woman with an incidentally discovered PAVM, initially treated with embolization and subsequent surgical resection. She remained asymptomatic for several years until progressive exertional dyspnea led to a diagnosis of severe precapillary PAH. Genetic testing identified a heterozygous BMPR2 splice-site variant (c.967 + 5G>A), previously reported in a PAH cohort but currently classified as a variant of uncertain significance. This report is notable for the delayed evolution from isolated PAVM to PAH in the context of a BMPR2 variant, raising the possibility of a mechanistic link outside the canonical HHT pathway. We review published reports of BMPR2-associated PAVMs, some of which include subtle HHT-like features, such as mucocutaneous telangiectases and epistaxis, despite negative testing for classical HHT genes. These observations suggest a potential phenocopy vascular syndrome driven by disruption of the shared bone morphogenetic protein 9 (BMP9)-ALK1 signaling axis. We also discuss the implications of sotatercept, a transforming growth factor-beta (TGF-β) superfamily ligand trap, which in this case was associated with symptomatic improvement and stable shunt burden. These findings contribute to the emerging recognition of atypical vascular phenotypes in BMPR2 variant carriers, particularly those presenting with PAVMs in the absence of HHT. It highlights the importance of considering genetic testing in isolated AVM presentations, as well as the need for longitudinal surveillance and mechanistic investigation into overlapping TGF-β/BMP signaling disorders.
Sundaravel S, Gupta N, Jain V
… +4 more, Sharma R, Jana M, Ramakrishnan L, Kabra M
Am J Med Genet A
· 2026 Jul · PMID 41795624
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Down syndrome (DS) is the most common chromosomal abnormality associated with intellectual disabilities. Many metabolic issues begin in childhood, and children without DS are reported to have a high prevalence of metabol...Down syndrome (DS) is the most common chromosomal abnormality associated with intellectual disabilities. Many metabolic issues begin in childhood, and children without DS are reported to have a high prevalence of metabolic syndrome (MS) according to various studies. However, our understanding of the risk of MS in children with DS is limited. A cross-sectional study assessed the prevalence of MS in DS children aged 10-18 during 2022-2024. Demographic details and anthropometric measurements were recorded for all participants. Fasting blood samples were collected for blood glucose, insulin, and lipid profile analysis. The modified NCEP-ATP III criteria were used to classify the MS. We also evaluated insulin resistance (IR) using HOMA-IR and body adiposity patterns with a DEXA scan in DS children aged 6-18. Seventy-six children aged 10-18 and 38 aged 6-9 were enrolled. The prevalence of MS was 18% in our cohort. Dyslipidemia (high triglycerides and low HDL) was observed in 21% and 15.8% of children aged 6-9 and 10-18, respectively. IR was observed in 27.6% and 7.8% of children aged 10-18 and 6-9, respectively. IR was positively correlated with BMI, whereas no correlation was observed with MS or dyslipidemia. Total body fat mass was positively correlated with MS. Our study observed a higher prevalence (18.0%) of MS than age-matched general population studies (pooled prevalence: 5.0%). Additionally, we observed a high prevalence of dyslipidemia and IR from 6 years of age. The results indicate the need to review the management guidelines and consider incorporating metabolic workups.
Babcock M, Daghsni M, Sebastian J
… +7 more, Lancaster E, Ghaloul-Gonzalez L, Ortiz D, Powell E, Bellissimo DB, Sahoo T, Yatsenko SA
Am J Med Genet A
· 2026 Jul · PMID 41795620
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Complex chromosomal rearrangements (CCRs) are structural variants involving multiple breakpoints. Among these, intrachromosomal balanced CCRs containing inversions pose significant diagnostic and interpretative challenge...Complex chromosomal rearrangements (CCRs) are structural variants involving multiple breakpoints. Among these, intrachromosomal balanced CCRs containing inversions pose significant diagnostic and interpretative challenges, as conventional cytogenetic methods including G-banded karyotype, FISH, and chromosomal microarray lack the resolution needed to determine their structural complexity. Paracentric inversions are traditionally associated with a negligible risk of a viable unbalanced offspring. Here, we describe a familial intrachromosomal rearrangement comprising a complex paracentric inversion of chromosome 6q, transmitted across multiple generations, that resulted in five affected children with recombinant chromosomes harboring reciprocal interstitial gains and losses on 6q. High-resolution optical genome mapping revealed a ~75 Mb parental balanced CCR, formed by multiple sequential paracentric inversions that contain a single ~13 Mb correctly oriented segment. Bias meiotic recombination between homologous chromosomes 6 within this segment is responsible for recurrent unbalanced products resembling recombinant chromosomes typically associated with pericentric inversions. These findings challenge the prevailing assumption that paracentric inversions rarely result in viable recombinant chromosomes and demonstrate how complex chromosomal architecture can directly influence meiotic behavior and reproductive outcomes. Our study underscores the importance of high-resolution genomic technologies for accurate diagnosis, interpretation of a molecular mechanism, and reproductive risk assessment in carriers of CCR.
Mahoney K, Crocker K, Blair J
… +8 more, Carratu K, Araya G, Kaur M, Raible SE, Luo M, Conway L, Hartman TR, Krantz ID
Am J Med Genet A
· 2026 Jul · PMID 41795619
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Waardenburg syndrome (WS) is a genetically heterogenous condition characterized by variable clinical features including congenital sensorineural hearing loss, pigmentation differences, dysmorphic features including dysto...Waardenburg syndrome (WS) is a genetically heterogenous condition characterized by variable clinical features including congenital sensorineural hearing loss, pigmentation differences, dysmorphic features including dystopia canthorum, and other manifestations. Pathogenic variants in WS genes, including PAX3, MITF, SOX10, EDNRB, EDN3, and KITLG, account for approximately 3% of congenital hearing loss cases. The genetic heterogeneity, variable expressivity, and different subtypes of WS have made diagnosis challenging. Recent literature suggests that W-index measurements evaluating for dystopia canthorum may not accurately differentiate between WS Types 1 and 2. This retrospective chart review investigated genotype-phenotype correlations in patients with WS at the Children's Hospital of Philadelphia. This study included 56 patients with a clinical or genetic diagnosis of WS. In addition, data was collected from 1744 patients with hearing loss and W-index measurements. Phenotypic characteristics were recorded for all 56 patients and an additional 230 patients with an elevated W-index (> 1.95) lacking a diagnosis of WS to determine the predictiveness of the W-index for WS. This study updates genotype-phenotype correlations in WS, characterizes novel variants, investigates the utility and predictiveness of W-index values in children with hearing loss, and provides rationale for increasing the W-index cutoff for dystopia canthorum to reduce negative testing results.
Villela D, Szeremeta M, Sobreira J
… +9 more, Alencar D, Martin R, Loureiro T, Bermeo D, Gomes M, de Castro LSS, Palmero EI, Scapulatempo-Neto C, Sobreira N
Am J Med Genet A
· 2026 Jul · PMID 41795183
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VariantMatcher is a web-based platform developed to share variant-level genomic data and phenotypic information. Here, we describe the experience of a clinical laboratory in Brazil, DASA, utilizing VariantMatcher to enha...VariantMatcher is a web-based platform developed to share variant-level genomic data and phenotypic information. Here, we describe the experience of a clinical laboratory in Brazil, DASA, utilizing VariantMatcher to enhance variant classification in a clinical setting. We retrospectively analyzed 3025 molecular genetic test results to identify variants classified as variants of uncertain significance (VUS). Of 2302 reported variants, 1679 were classified as VUS. Next, we selected the 542 VUS not described in gnomAD to investigate their presence in VariantMatcher. Of these 542, 80 variants were present in VariantMatcher. Sixty-three of them were identified in individuals with a phenotypic overlap. Further investigation of the phenotypic features of individuals with the same variants led to the reclassification of 20 (32%) of the 63 variants. Notably, most of the reclassifications helped rule out the queried variant as causative for the phenotype being investigated, particularly for autosomal or X-linked dominant diseases with early onset and complete penetrance. Our experience supports the benefits of data sharing in the clinical setting, which can improve variant classification accuracy and provide more precise guidance for informed clinical decision-making.
Feng Z, Liu W, Li H
… +5 more, Wu S, Zhou R, Chen X, Yao Y, Kong X
Am J Med Genet A
· 2026 Jul · PMID 41795174
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Evaluate the application efficacy of trio exome sequencing (Trio-ES) in prenatal families with a history of developmental delay/intellectual disability (DD/ID). This cohort study enrolled prenatal families with a family...Evaluate the application efficacy of trio exome sequencing (Trio-ES) in prenatal families with a history of developmental delay/intellectual disability (DD/ID). This cohort study enrolled prenatal families with a family history of DD/ID from a single center between January 2020 and May 2025. We included 104 prenatal families that had excluded copy number variation abnormalities but had not undergone single nucleotide variant testing. Based on family history, these families were divided into two groups: those with a history of DD/ID births but phenotypically normal parents (lacking proband samples), and those without a history of DD/ID births but with one or both parents having ID. The overall positive rate of prenatal Trio-ES among 104 families with a history of DD/ID was 21.15% (22/104). Among 81 families with a history of DD/ID births but phenotypically normal parents, the positive rate was 13.58% (11/81), including 7.41% (6/81) affected fetuses and 6.17% (5/81) only parents as carriers, both primarily exhibiting a recessive inheritance pattern. Additionally, the positive rate in non-syndromic DD/ID families was 11.54% (6/52), while it reached 17.24% (5/29) in syndromic DD/ID families (associated with epilepsy, dystonia, hearing impairment, abnormal head circumference, etc.). Among 23 families without a history of DD/ID births but with one or both parents having ID, the positive rate significantly increased to 47.83% (11/23), primarily driven by dominant variants. This study represents the first focused evaluation of the clinical utility of Trio-ES in prenatal families with a history of DD/ID when proband samples are unavailable. We recommend actively employing Trio-ES for prenatal genetic evaluation in such families, particularly those presenting with a syndromic phenotype.
Sheth F, Shah J, Muranjan M
… +9 more, Liehr T, Padutsch N, Mane S, Ng SME, Li P, Desai M, Kansara H, Sheth JJ, Sheth H
Am J Med Genet A
· 2026 Jul · PMID 41755742
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Molecular characterization of balanced complex chromosomal rearrangements (CCR) aids in understanding the pathophysiological mechanism and corresponding genotype-phenotype correlations. The present case describes a male...Molecular characterization of balanced complex chromosomal rearrangements (CCR) aids in understanding the pathophysiological mechanism and corresponding genotype-phenotype correlations. The present case describes a male child with intellectual disability, developmental delay, and dysmorphism. A thorough and sequential genetic evaluation using karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray (CMA), and long read sequencing (LRS) identified a genomically balanced CCR. The CCR involved eight chromosomes, the largest to be documented till date for chromoanagenesis and being balanced despite the high level of complex chromosomal involvement. Translocations accounted for the majority of the rearrangements along with an insertion, inversion, and a small deletion likely driven by chromoplexy. Although the CCR was genomically balanced, it may still result in functionally significant genomic consequences including gene disruptions, gene fusions, and position effects. Long read whole genome sequencing using PacBio was used for breakpoint characterization that revealed three protein-coding genes to be disrupted, namely, NLGN4X, LAMA4, and ALG6. Of these, a candidate association was observed for the NLGN4X gene with the intellectual disability phenotype reported in the proband, which is likely due to disruption of transcription and nonsense mediated decay. We show combinatorial application of advanced genomic technologies with orthogonal cytogenetic techniques in delineating balanced CCRs and understanding the biological and potential clinical implications of balanced yet functionally disruptive CCRs.
de Arruda Sampaio PHM, Moreno CAM, di Pace F
… +4 more, Dousseau GC, Camelo CG, Schlesinger D, Zanoteli E
Am J Med Genet A
· 2026 Jul · PMID 41744056
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Pathogenic variants in PIGG (phosphatidylinositol glycan anchor biosynthesis, class G) disrupt glycosylphosphatidylinositol (GPI) anchoring of cell-surface proteins. Recently, biallelic PIGG variants have been linked to...Pathogenic variants in PIGG (phosphatidylinositol glycan anchor biosynthesis, class G) disrupt glycosylphosphatidylinositol (GPI) anchoring of cell-surface proteins. Recently, biallelic PIGG variants have been linked to motor neuropathy with conduction block and temporal dispersion, suggesting a role for defective GPI anchoring in peripheral nerve function. We describe a 27-year-old woman carrying a homozygous nonsense variant in PIGG, c.1515G>A (p.Trp505*), presenting with continuous lower limb myokymia, gait ataxia, tremor and distal weakness since early adolescence. Electrophysiological evaluation revealed widespread myokymic discharges on electromyography, consistent with peripheral nerve hyperexcitability, and a pure motor polyneuropathy with temporal dispersion. This case report expands the clinical spectrum of PIGG-related disorders by identifying peripheral nerve hyperexcitability as a defining feature. The potential mechanistic link between defective GPI anchoring and neuronal hyperexcitability mediated through impaired function of GPI-anchored proteins such as contactin-1 and contactin-2 offers a compelling hypothesis connecting peripheral neuropathy, hyperexcitability, and cerebellar dysfunction.
Ren Y, Niu W, Cao Y
… +3 more, Zhang Y, Hua J, Wang H
Am J Med Genet A
· 2026 Jul · PMID 41744052
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Variants in the keratin 6A (KRT6A) gene are a major cause of pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by nail hypertrophy and other ectodermal abnormalities. This study aimed to ident...Variants in the keratin 6A (KRT6A) gene are a major cause of pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by nail hypertrophy and other ectodermal abnormalities. This study aimed to identify the causative mutation in a PC family and investigate the underlying pathogenic mechanism. We performed exome sequencing on this PC pedigree and validated candidate variations using Sanger sequencing. In silico predictions and in vitro experiments showed that the heterozygous missense variant c.512A>G in KRT6A was pathogenic, inducing protein aggregation and disrupting filamentous network structures. Enrichment analysis suggested that the PPAR signaling pathway played a crucial role in PC, with decreased expression of PPARβ/δ in HeLa cells. Comparative analysis of PC patients carrying the p.Asn171 variant revealed marked heterogeneity in clinical manifestations. Notably, oral leukokeratosis, a common phenotype in KRT6A mutation carriers, was not observed in the patients in this study. Interestingly, one patient presented with small papules around the lips and nasal bridge. We conclude that the c.512A>G variant in KRT6A is the genetic cause of this PC family, diagnosed as PC-K6a subtype. This study expands the phenotypic spectrum of congenital PC and suggests the PPAR signaling pathway as a potential therapeutic target.
Kilich G, Jadhav T, Maurer K
… +8 more, Breen C, Jammihal T, Schindewolf E, Ganetzky RD, Vanderver A, Skraban C, Rajagopalan R, Sullivan KE
Am J Med Genet A
· 2026 Jul · PMID 41741356
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Pathogenic, biallelic variants in LIG3 are known to cause Mitochondrial DNA Depletion syndrome 20 with variable expression and severity. We describe a child with progressive encephalopathy, cataracts, movement disorder,...Pathogenic, biallelic variants in LIG3 are known to cause Mitochondrial DNA Depletion syndrome 20 with variable expression and severity. We describe a child with progressive encephalopathy, cataracts, movement disorder, endocrine dysfunction, and immunodeficiency who remained undiagnosed despite multiple negative clinical genomic diagnostic studies. Research reanalysis of PacBio long-read genome sequencing data identified compound heterozygous LIG3 variants, including a splice variant and a novel 98 bp insertion. Western blot confirmed loss of LIG3 protein expression and RNA-seq demonstrated aberrant transcripts. Muscle biopsy revealed mitochondrial dysfunction, with COX-deficient fibers and complex IV deficiency. Notably, this is the first reported association of LIG3 deficiency with immunologic and endocrine abnormalities, emphasizing the importance of a broad approach to phenotype-genotype.
Hu J, Dawood M, Mehta HH
… +9 more, Pasham D, Kaur M, Kalra D, Walker K, Gingras MC, Lupski JR, Sabo A, Pehlivan D, Gibbs RA
Am J Med Genet A
· 2026 Jul · PMID 41738116
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Xia-Gibbs Syndrome (XGS; MIM: 615829) is a rare neurodevelopment disorder (NDD) caused by de novo pathogenic variants in the single coding exon of the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene. In this study, w...Xia-Gibbs Syndrome (XGS; MIM: 615829) is a rare neurodevelopment disorder (NDD) caused by de novo pathogenic variants in the single coding exon of the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene. In this study, we investigate a rare case of double mosaicism in a 10-year-old female with XGS. The proband presented with characteristic clinical findings observed in XGS, including severe developmental delay, hypotonia, seizures, and dysmorphic features. Initial clinical genetic testing reported two adjacent de novo arising variants in AHDC1 (c.1167delG and c.1169delC), each present with an approximately 30%-36% allelic fraction in genomic DNA from a blood sample. In order to establish the haplotype phase of the variants, we performed long-read whole genome sequencing of DNA from an additional blood sample and short-read amplicon sequencing with blood and buccal swab samples. These data indicated that the adjacent variants are in trans on the same parental haplotype, likely originating in the zygote. These findings indicate a rare occurrence of double mosaicism and provide insights into the mechanisms behind somatic mutations influencing early development. The case underscores the importance of advanced molecular techniques in resolving complex genetic events and their impact on clinical presentations in XGS.
Kashevarova AA, Minaycheva LI, Fonova EA
… +9 more, Vasilyeva OY, Zarubin AA, Ravzhaeva EG, Petlina EY, Sukhanova NN, Zuev AS, Yamin VA, Seitova GN, Lebedev IN
Am J Med Genet A
· 2026 Jul · PMID 41738068
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To date, only two families with variants in the IQSEC1 gene associated with intellectual developmental disorder with short stature and behavioral abnormalities (IDDSSBA) have been described. Here, we report an 8-year-old...To date, only two families with variants in the IQSEC1 gene associated with intellectual developmental disorder with short stature and behavioral abnormalities (IDDSSBA) have been described. Here, we report an 8-year-old boy with short stature, speech delay, dysmorphic facial features, hypotonia, and behavioral disorders, as well as corpus callosum dysgenesis associated with compound heterozygous variants Pro1095ArgfsTer97 and Thr485Met in the IQSEC1 gene. To our knowledge this is the first report of brain anomalies associated with IQSEC1 variants, highlighting the need for MRI in affected patients.
Esener Z, Öztürk M, Habiloğlu E
… +6 more, Tekmenuray-Ünal A, Ünsel-Bolat G, Eşmeli F, Sezer A, Bulut E, Bolat H
Am J Med Genet A
· 2026 Jul · PMID 41732832
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ATP6V0A2-related cutis laxa is a rare autosomal recessive disorder characterized by connective tissue abnormalities, developmental delay, and neurological features. While multiple sequence variants have been reported, ex...ATP6V0A2-related cutis laxa is a rare autosomal recessive disorder characterized by connective tissue abnormalities, developmental delay, and neurological features. While multiple sequence variants have been reported, exon-level deletions are rarely documented, and their clinical significance remains largely unknown. This study aims to present the clinical and molecular characteristics of a novel frameshift variant and recurrent exon 16 deletions in the ATP6V0A2 gene, to investigate a potential founder effect in southeastern Türkiye, and to contribute to the expanding genotype-phenotype correlation in ATP6V0A2-related cutis laxa. Ten cases from six unrelated families were evaluated. Exome sequencing, clinical exome sequencing, long-range polymerase chain reaction, gel electrophoresis, and haplotype analysis were performed. Variant interpretation followed ACMG and ClinGen guidelines. Clinical features were assessed through physical examination, developmental history, and neuroimaging. A novel homozygous frameshift variant (c.235del, p.Leu79Phefs*13) associated with severe neurological regression was identified in one case. Nine individuals carried a recurrent homozygous 380 bp deletion spanning exon 16 (c.1936-147_2055+113del). In our study, neurological regression-a feature rarely reported in the literature-was noted in two older patients. Haplotype analysis revealed shared homozygous regions in three cases, suggesting a founder effect. This cohort represents the largest reported series of ATP6V0A2-CL cases with exon 16 deletion to date. This study expands the genotypic and phenotypic spectrum of ATP6V0A2-CL and underscores the importance of copy number variation detection in next-generation sequencing-based diagnostics. The identification of a recurrent exon 16 deletion and shared haplotypes provides evidence for a founder effect in southeastern Türkiye and supports the implementation of population-specific screening for this variant.
Am J Med Genet A
· 2026 Jul · PMID 41730799
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Cockayne syndrome (CS) is an ultrarare genetic disorder associated with genes encoding proteins involved in DNA repair. The clinical course of CS involves neurodevelopmental and neurodegenerative features, including swal...Cockayne syndrome (CS) is an ultrarare genetic disorder associated with genes encoding proteins involved in DNA repair. The clinical course of CS involves neurodevelopmental and neurodegenerative features, including swallowing and communication impairments. The aim of this article is to provide an overview of the literature relating to deglutition and communication in individuals with CS to guide management of this complex disease and highlight clinical knowledge gaps. Pertinent articles and case reports on CS, published between 1990 and 2024, were reviewed in three domains: etiology, dysphagia, and communication. Our review indicates that individuals with CS experience significant early delays and later declines in communication and swallowing abilities. Larger cohort studies document the general occurrence of these impairments, while smaller case series and single-case reports have examined some of these issues in greater detail. We did not find larger cohort reports systematically assessing these domains quantitatively, indicating significant knowledge gaps regarding clinical complications impacting quality of life. Qualitative documentation of swallowing and communication impairments reported to date supports speech-language pathologists' inclusion on multidisciplinary teams caring for individuals with CS. Given the paucity of literature systematically characterizing the swallowing and communication of individuals with CS, further investigation is warranted to provide more targeted care.
Am J Med Genet A
· 2026 Jul · PMID 41730779
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To enhance the diagnosis, management, and monitoring of Chinese children with chromosome 15q11-q13 duplication syndrome (dup15q) by analyzing their genetic and clinical characteristics. In this study, one Chinese prenata...To enhance the diagnosis, management, and monitoring of Chinese children with chromosome 15q11-q13 duplication syndrome (dup15q) by analyzing their genetic and clinical characteristics. In this study, one Chinese prenatal case and 21 postnatal cases genetically diagnosed with dup15q syndrome underwent a detailed assessment of genetic and clinical characteristics. Most patients had normal prenatal (12/22, 54.5%) and neonatal (14/21, 66.7%) histories. Most symptoms were developmental delays (motor: 18/21, 85.7%; cognition: 13/21, 61.9%; language: 12/21, 57.1%). Other common features included autism spectrum disorder (ASD)-related behaviors (10/21, 47.6%) and seizures (7/21, 33.3%). Trisomy microduplications accounted for 54.5% (12/22), and tetrasomy microduplications accounted for 40.9% (9/22) of cases. We compared the phenotypic differences between the two groups using a composite score. One rare case of paternal duplication presented with early-onset obesity and tapered fingers resembling Prader-Willi syndrome (PWS). In addition, non-invasive prenatal testing (NIPT) detected int dup(15) in prenatal cases. Some patients with epilepsy were well controlled without anti-seizure drugs or monotherapy (3/7, 42.8%), while others had refractory epilepsy. Chinese children with dup15q exhibited high clinical heterogeneity, including multisystem developmental delays, ASD-related symptoms, and seizures. Phenotypic severity is influenced by multiple factors. NIPT may show positive findings, and chromosomal microarray analysis (CMA) combined with methylation analysis is important.
Abi Nassif M, Kaul A, Dorfman L
… +1 more, El-Chammas K
Am J Med Genet A
· 2026 Jul · PMID 41724656
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Rubinstein-Taybi syndrome is a rare genetic condition associated with a wide range of physical, cognitive, and developmental impairments, yet its gastrointestinal manifestations remain poorly characterized. Case reports...Rubinstein-Taybi syndrome is a rare genetic condition associated with a wide range of physical, cognitive, and developmental impairments, yet its gastrointestinal manifestations remain poorly characterized. Case reports and small series suggest a high prevalence of gastroesophageal reflux, constipation, dysphagia, and nutritional compromise, but no large cohort has examined these symptoms in detail. This study aimed to characterize gastrointestinal and nutritional comorbidities in children with Rubinstein-Taybi syndrome seen at a tertiary pediatric center between 2013 and 2023. Among 85 affected patients, 46 (54%) reported gastrointestinal symptoms, and 31 (66%) were evaluated in the Gastroenterology clinic. Symptoms frequently predated the genetic diagnosis. Constipation was most common, followed by reflux symptoms, dysphagia, vomiting, and feeding intolerance or poor weight gain. Most patients underwent at least one diagnostic evaluation, including upper gastrointestinal imaging, video swallow studies, or esophagogastroduodenoscopy. Nearly half required gastrostomy tube support, typically in later childhood, with subsequent improvements in weight and body mass index z-scores and successful transitions to partial or full oral intake in some cases. Oral-fed patients demonstrated modest growth improvement over shorter follow-up intervals. These findings highlight a substantial gastrointestinal disease burden in Rubinstein-Taybi syndrome and underscore the importance of early recognition and multidisciplinary management.
Liang J, Wu J, Zhang L
… +4 more, Qi Y, Wang Y, Cao X, Zhai J
Am J Med Genet A
· 2026 Jun · PMID 41724599
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To investigate the correlation between genetic abnormalities and fetal genitourinary (GU) anomalies in Eastern China and to provide assistance for the clinical management of fetuses with different types of GU anomalies....To investigate the correlation between genetic abnormalities and fetal genitourinary (GU) anomalies in Eastern China and to provide assistance for the clinical management of fetuses with different types of GU anomalies. Five hundred forty-five fetuses with GU anomalies were enrolled, undergoing karyotyping, copy number variation sequencing (CNV-seq) or chromosomal microarray analysis (CMA), and trio-exome sequencing (trio-ES), and received long-term follow-ups from 6 months to 7 years. The top five GU anomalies were hydronephrosis, renal agenesis, multicystic dysplastic kidney, genital cysts, and genital abnormalities. 4.77% (19/398) of chromosomal abnormalities were detected by karyotyping, and 39 CNVs were revealed in 354 cases by CNV-seq/CMA simultaneously, with 6.50% (23/354) of additional CNVs. Genetic abnormalities were more frequent in reproductive system anomalies, nonisolated, and multiple GU anomalies. Two of eight with pathogenic/likely pathogenic genes were additionally detected. Five hundred thirty-four pregnancy outcomes were obtained, including 418 (76.70%) live births with favorable outcomes, two (0.37%) intrauterine fetal deaths, and 114 (20.92%) terminations mainly due to genetic abnormalities or nonisolated anomalies. The fetuses with reproductive system anomalies, nonisolated, and multiple GU anomalies were associated with genetic abnormalities. Therefore, a closed-loop management strategy including "diagnosis-assessment-intervention-follow-up" should be provided for fetuses with GU anomalies from pregnancy to postpartum period.
Xiong F, Wang Q, Wang SQ
… +4 more, Zheng M, Zhong HY, Zou ML, Yuan SM
Am J Med Genet A
· 2026 Jul · PMID 41724598
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Postzygotic mutations of the PIK3CA gene constitutively activate the PI3K/AKT/mTOR pathway in patients with PIK3CA-related overgrowth spectrum (PROS), causing congenital mosaic tissue overgrowth. We established primary f...Postzygotic mutations of the PIK3CA gene constitutively activate the PI3K/AKT/mTOR pathway in patients with PIK3CA-related overgrowth spectrum (PROS), causing congenital mosaic tissue overgrowth. We established primary fibroblast cells from a patient with a novel somatic frameshift mutation (c.3190_3191insA, [p.H1065fs]) in PIK3CA, in which PI3K/AKT/mTOR signaling is activated compared to control fibroblasts. We assessed the therapeutic effects of three compounds (BYL719, ARQ092, and rapamycin) on the PI3K/AKT/mTOR signaling pathway and cell growth. Notably, BYL719 is more effective at inhibiting the overactivation of all key signaling molecules in the pathway at lower concentrations in patient-derived fibroblasts, while showing no significant effect on control fibroblasts. The insertion frameshift mutation is not located within the five domains, but it is a gain-of-function PIK3CA mutation contributing to PROS development. The results further confirmed the obvious advantages of the compound in targeted therapy for PROS patients.