Am J Med Genet A
· 2026 Jun · PMID 41641652
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RASopathies are a clinically and genetically heterogeneous group of conditions caused by pathogenic variants in genes encoding RAS/MAPK pathway components. Liver involvement has been reported, but systematic evaluation o...RASopathies are a clinically and genetically heterogeneous group of conditions caused by pathogenic variants in genes encoding RAS/MAPK pathway components. Liver involvement has been reported, but systematic evaluation of liver involvement in individuals with RASopathies has not been performed, limiting anticipatory guidance and screening development. We aim to characterize liver involvement in RASopathies. The cohort consisted of individuals with molecularly confirmed RASopathy evaluated at a single center between January 2006 and October 2024. Clinical histories were abstracted from the medical record. The cohort included 192 participants. Liver involvement was noted in 36.5%. Neonatal hyperbilirubinemia was present in 33.3%, and 24% required phototherapy, representing a significantly increased risk (OR 7.1, 95% confidence interval [CI] 4.66-10.95, p < 0.0001). Other liver pathology was noted in 15 participants (7.8%), including elevated aminotransferases (n = 9) and cholestasis (n = 7). Participants with BRAF variants were more likely to have cholestasis than those with other genotypes (OR 6.2, 95% CI 1.45-24.03, p = 0.038). Comprehensive evaluation of liver involvement in a large RASopathy cohort revealed a strong association with neonatal liver disease, most commonly hyperbilirubinemia and cholestasis. Evaluation for liver disease may be warranted in infants with RASopathies, especially individuals with BRAF variants.
Schecter DR, Zamalin D, Abdow VP
… +4 more, Francisco B, Drago M, Ratner V, Tinker RJ
Am J Med Genet A
· 2026 Jun · PMID 41635268
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Radioulnar synostosis with amegakaryocytic thrombocytopenia type 2 (RUSAT-2) is a rare inherited bone marrow failure syndrome characterized by congenital or progressive thrombocytopenia, frequent radioulnar synostosis, a...Radioulnar synostosis with amegakaryocytic thrombocytopenia type 2 (RUSAT-2) is a rare inherited bone marrow failure syndrome characterized by congenital or progressive thrombocytopenia, frequent radioulnar synostosis, and variable multisystem involvement. It is caused by heterozygous germline pathogenic variants in the MDS1 and EVI1 Complex Locus (MECOM) gene, which encodes transcription factors essential for hematopoietic stem cell regulation and embryonic development. Disruption of highly conserved zinc finger domains within MECOM impairs long-term hematopoietic stem cell maintenance, leading to amegakaryocytic thrombocytopenia and, in many cases, progression to pancytopenia. Although MECOM is also implicated in leukemogenesis through somatic dysregulation, germline variants associated with RUSAT-2 result in a distinct developmental and hematologic phenotype with highly variable penetrance and age of onset. As of 2025, there were approximately 66 reported cases of RUSAT-2 reported in the literature, with clinical severity ranging from isolated thrombocytopenia to early-onset bone marrow failure requiring hematopoietic stem cell transplantation. This review summarizes the current understanding of the genetic basis, clinical manifestations, differential diagnosis, clinical course, management considerations, and outstanding mechanistic questions surrounding RUSAT-2.
Smith K, Abruzzo MA, Erickson RP
… +2 more, Thomas A, Kukolich M
Am J Med Genet A
· 2026 Jun · PMID 41630180
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The purpose of this study is to explore the phenotypic spectrum observed in individuals and between families with confirmed variants in the T-Box Transcription Factor 22 gene (TBX22). Pathogenic variants in TBX22 have be...The purpose of this study is to explore the phenotypic spectrum observed in individuals and between families with confirmed variants in the T-Box Transcription Factor 22 gene (TBX22). Pathogenic variants in TBX22 have been identified in individuals with classic X-linked cleft palate (CPX) and also in Abruzzo-Erickson Syndrome (ABERS). We compare the phenotypic features of a newly suspected family with ABERS to those of the original family with ABERS to help determine if family-specific pathogenic variants in TBX22 are the cause of ABERS. Furthermore, we discuss possible mechanisms of action of the identified TBX22 variants. We conducted an observational case series in a new family (Family B) suspected of having ABERS, and a retrospective review of participants in the original family with ABERS (Family A), as described by Abruzzo and Erickson (1977). Thirteen individuals from two different families were included in this case series. As previously reported in 2013, DNA samples from four individuals in Family A were screened for variants in TBX22, and each was found to carry the same unique pathogenic variant. Five individuals from Family B were screened for variants in TBX22, and the four with abnormal features were found to be positive for a new pathogenic variant; however, the variant segregating in this family differed from the one present in Family A. Despite this, there was considerable overlap between Family A and Family B in phenotypic features. Thus, we hypothesize that gain-of-function pathogenic variants in TBX22 are the probable cause of ABERS in both Family A and Family B.
Okamoto N, Nishi E, Hasegawa Y
… +1 more, Hayashi S
Am J Med Genet A
· 2026 Jun · PMID 41622991
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DeSanto-Shinawi syndrome is a rare genetic disorder caused by pathogenic variants or deletions involving the WAC gene, located on chromosome 10p12.1, and is characterized by developmental delay, intellectual disability,...DeSanto-Shinawi syndrome is a rare genetic disorder caused by pathogenic variants or deletions involving the WAC gene, located on chromosome 10p12.1, and is characterized by developmental delay, intellectual disability, and distinctive dysmorphic features. In addition to deletions encompassing WAC, several proximal deletions on chromosome 10 that exclude WAC have also been reported. Here, we describe a patient with a microdeletion of chromosome 10p11.23-p11.21 spanning approximately 4.2 Mb. The patient exhibited intellectual disability, agenesis of the corpus callosum, and congenital heart disease. The deleted region includes the following protein-coding genes: ZNF438, ZEB1, ARHGAP12, KIF5B, EPC1, CCDC7, ITGB1, NRP1, and PARD3, while WAC was preserved. Pathogenic variants or deletions of ZEB1 are known to cause corneal abnormalities and agenesis of the corpus callosum, whereas loss of NRP1 has been implicated in the pathogenesis of congenital heart disease. We therefore hypothesize that haploinsufficiency of multiple genes within the deleted region-particularly ZEB1, EPC1, KIF5B, and NRP1-may collectively contribute to the observed clinical phenotype. These findings suggest that microdeletions involving chromosome 10p11.2 are associated with a phenotype distinct from that of DeSanto-Shinawi syndrome.
Arish S, Nobakht R, Mokabber H
… +5 more, Nojedeh ST, Davarnia S, Hasanzadeh S, Kalhor H, Davarnia B
Am J Med Genet A
· 2026 Jun · PMID 41603389
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TBC1 domain-containing kinase (TBCK; MIM #616900) is implicated in autosomal recessive neurodevelopmental disorders with hypotonia and developmental delay. TBCK regulates mTOR signaling, lysosomal activity, and intracell...TBC1 domain-containing kinase (TBCK; MIM #616900) is implicated in autosomal recessive neurodevelopmental disorders with hypotonia and developmental delay. TBCK regulates mTOR signaling, lysosomal activity, and intracellular trafficking, but the full spectrum of pathogenic variants remains poorly understood. We investigated a consanguineous Iranian family with psychomotor delay. Whole exome sequencing (WES) identified a candidate TBCK variant, confirmed by Sanger sequencing. Functional studies were performed using amniotic fluid-derived cell culture, Western blotting, protein structural modeling, and molecular docking analyses. A novel homozygous frameshift variant, TBCK (NM_001163435.3): c.1969dupT (p.Cys657Leufs*17), was detected and absent from population databases. Clinically, the proband presented with severe developmental delay, hypotonia, seizures, and facial dysmorphism, and died at 9 months. Western blotting showed a significant decrease in TBCK expression (p < 0.007). Structural analysis of a theoretically modeled truncated protein indicated C-terminal truncation with loss of critical domains, while in silico docking demonstrated reduced binding affinity between mutant TBCK and Rab1B, suggesting impaired Rab-mediated trafficking. This study reports a novel pathogenic TBCK variant associated with severe neurodevelopmental delay, contributing to the clinical and molecular spectrum of TBCK syndrome. Our findings underscore the importance of genetic testing in rare neurodevelopmental disorders and provide insight into the molecular mechanisms underlying TBCK dysfunction.
Gowda VK, Roy A, Disha B
… +2 more, Govindaraj P, Srinivasan VM
Am J Med Genet A
· 2026 Jun · PMID 41603106
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Biallelic variants in the STAMBP gene are known to cause Microcephaly-capillary malformation syndrome (MICCAP syndrome). Here we report an 18-month-old female with a novel splice site variant, c.376-1G>A in intron-4, wit...Biallelic variants in the STAMBP gene are known to cause Microcephaly-capillary malformation syndrome (MICCAP syndrome). Here we report an 18-month-old female with a novel splice site variant, c.376-1G>A in intron-4, with the phenotype of a patient who presented to us with fetal onset growth retardation, developmental delay, drug-resistant seizures, multiple capillary malformations, dysmorphism, tone abnormalities, and distal skeletal and nail abnormalities. Functional studies by RNA analysis and quantitative polymerase chain reaction (qPCR) showed that the variant leads to loss of function. The clinical features noted in this child strongly overlapped with the phenotypes reported in the literature, except for absent dentition and retinal dystrophy-like findings on fundus examination. A total of 22 cases have been reported in the literature. We present a detailed description of an Indian child, expanding the clinical and molecular spectrum of STAMBP-related disease.
Kanno M, Sato H, Uemura Y
… +12 more, Meguro T, Ishigaki R, Kawasaki N, Abiko M, Suzuki K, Numakura C, Tamiya G, Takayama J, Kure S, Saijo N, Kikuchi A, Mitsui T
Am J Med Genet A
· 2026 Jun · PMID 41589511
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Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) is a congenital disorder characterized by lymphedema, telangiectasia, and hypotrichosis or alopecia, caused by mutations in the SRY-related high-mobility group box...Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) is a congenital disorder characterized by lymphedema, telangiectasia, and hypotrichosis or alopecia, caused by mutations in the SRY-related high-mobility group box (SOX) 18 gene. We report the case of a 10-year-old boy who presented with aortic valve regurgitation, marbled skin, minor anomalies, and iron-deficiency anemia due to frequent mucosal bleeding. At 5 years of age, he experienced significant hemostatic difficulties following the extraction of a deciduous tooth. The usual doses of iron supplementation did not cure his iron-deficiency anemia. Blood coagulation analysis revealed a decreased platelet agglutination capacity, associated with reduced von Willebrand factor (vWF) antigen levels and activity. Whole-genome sequencing at the age of 15 years did not identify any pathogenic variants in the VWF gene. However, this analysis revealed a heterozygous pathogenic variant of SOX18 (NM_018419.3: c.481C>T, p.Gln161Ter), which led to the diagnosis of HLTS. SOX18 plays a significant role in VWF expression in stem cells. vWF replacement therapy facilitated safe tooth extraction and stabilized hemoglobin levels. Decreased vWF may be a complication of HLTS, and vWF replacement therapy can significantly improve patients' quality of life.
Curlee MS, Siegel A, Little P
… +9 more, Toledo-Tamula MA, Martin S, Gross AM, Yohe ME, Aryavand M, Frone MN, Ney GM, Stewart DR, Wolters PL
Am J Med Genet A
· 2026 May · PMID 41578731
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Costello syndrome (CS) is a rare RASopathy that is typically associated with mild to moderate cognitive impairment. Based on detailed neuropsychological testing, this case series describes variability in the neurobehavio...Costello syndrome (CS) is a rare RASopathy that is typically associated with mild to moderate cognitive impairment. Based on detailed neuropsychological testing, this case series describes variability in the neurobehavioral presentations of three unrelated individuals with different pathogenic HRAS variants that cause CS. Results demonstrate a wide range of functioning among people with CS (extremely low to superior ranges) and describe the first cognitive testing results for an individual with HRAS c.179G>A, p.Gly60Asp. Patient-reported social, emotional, and quality of life outcomes also are discussed. These cases highlight the potential for above average cognitive functioning, the importance of flexible neurobehavioral assessment methods, and key quality of life and mental health domains to evaluate in individuals with CS.
Battiston GS, Araujo CS, Romera FA
… +10 more, Ferreira AL, Martins ÉT, de Aguiar CG, Santos JEM, Ragazzini R, Costa-Nobre DT, Prestes ACY, de Oliveira AC, Perrone E, Melo DG
Am J Med Genet A
· 2026 May · PMID 41572728
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Marden-Walker syndrome (MWS; OMIM 248700) is an extremely rare congenital disorder characterized by multiple joint contractures, craniofacial dysmorphism, neurological abnormalities, and multisystem involvement. Although...Marden-Walker syndrome (MWS; OMIM 248700) is an extremely rare congenital disorder characterized by multiple joint contractures, craniofacial dysmorphism, neurological abnormalities, and multisystem involvement. Although historically diagnosed on clinical grounds, only a few cases have been molecularly confirmed. Here, we describe a Brazilian female infant with classic manifestations of MWS, carrying a heterozygous pathogenic variant in the PIEZO2 gene not previously reported in MWS. To our knowledge, this is the first molecularly confirmed MWS case from Brazil, thus expanding both the genotype-phenotype spectrum and geographic distribution of PIEZO2-related disorders. Comparative analysis of previously reported molecularly confirmed cases reveals shared core features and highlights the prominent neurological involvement observed in our patient. A review of individuals with the same PIEZO2 variant demonstrates marked phenotypic variability-from Gordon syndrome to distal arthrogryposis type 5-underscoring allelic heterogeneity and variable expressivity. This case refines the phenotypic spectrum of PIEZO2-related disorders and illustrates how allelic heterogeneity contributes to wide clinical variability, while also underscoring the importance of including underrepresented populations in variant interpretation.
Am J Med Genet A
· 2026 May · PMID 41572647
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Pathogenic variants in the SCN5A gene and its subunits have been identified in individuals with Brugada Syndrome. One such SCN5A variant, c.689T>C(p.Ile230Thr), was previously reported as disease-causing only in homozygo...Pathogenic variants in the SCN5A gene and its subunits have been identified in individuals with Brugada Syndrome. One such SCN5A variant, c.689T>C(p.Ile230Thr), was previously reported as disease-causing only in homozygous individuals, with heterozygous carriers being unaffected. Presently, we discuss the case of an adolescent patient who presented for further evaluation of pre-syncopal episodes with ECG findings consistent with Brugada pattern who on further genetic evaluation was found to be a heterozygous carrier of the pathogenic SCN5A c.689T>C(p.Ile230Thr) variant. This unique case allows us to think differently about heterozygous carriers for this specific mutation, and while the risk for developing a life-threatening arrhythmia may be low, heterozygous carriers may benefit from clinical monitoring to reduce the potential for adverse cardiac outcomes. A 17-year-old male presented after a pre-syncopal episode whose ECG demonstrated sinus bradycardia and type 1 Brugada pattern. Genetic testing revealed this patient to be a heterozygous carrier of a pathogenic SCN5A variant (c.689T>C(p.Ile230Thr)) which was also found in his father and brother, neither of whom had symptoms but did have ECG changes. He was diagnosed with Brugada Syndrome and advised to avoid known triggers. This case highlights the potential risk of severe cardiac arrhythmias in heterozygous carriers of the SCN5A c.689T>C (p.Ile230Thr) variant, previously thought to be benign. The 17-year-old patient, along with his asymptomatic father and brother who also carried the variant, exhibited ECG changes consistent with Brugada pattern. This finding suggests that heterozygous carriers may require closer monitoring and early intervention to prevent future life-threatening cardiac events.
Abdalla Moady T, Hershkovitz T, Habib C
… +8 more, Attias O, Hadash A, Tal G, Khoury A, Ben-Ari J, Eytan D, Paperna T, Weiss K
Am J Med Genet A
· 2026 Jun · PMID 41572441
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Few studies describe the impact of rapid exome sequencing (ES) on pediatric cardiomyopathy in urgent clinical settings. Here, we retrospectively report the impact of rapid singleton ES in pediatric patients presented wit...Few studies describe the impact of rapid exome sequencing (ES) on pediatric cardiomyopathy in urgent clinical settings. Here, we retrospectively report the impact of rapid singleton ES in pediatric patients presented with acute heart failure and isolated cardiomyopathy or myocarditis, between 2021 and 2023 at a single tertiary care center. A total of nine patients were included; age range: 5 days-11 years (median 42 days). Eight patients (88.8%) presented in the first year of life. The turnaround time for the ES results was 5-14 days (median 9 days). The diagnostic yield was 5/9 (55.5%), confirming primary cardiomyopathy. The majority had dominant disorders (ACTC1, MYBCP3, TNNI3, and NKX2-5), with two (22.2%) occurring de novo. One patient had a recessive condition (MYBPC3). In three patients (33.3%) who rapidly deteriorated during hospitalization, ES results had a major impact on immediate medical management. In most patients, the diagnosis led to the avoidance of further metabolic workup, cardiac magnetic imaging and vitamin treatment. In two families with no prior history of cardiomyopathy, at-risk relatives were advised to initiate cardiac surveillance. Overall the results show high clinical impact due to a shorter time to diagnosis, a high diagnostic yield, an improved therapeutic approach, in addition to the facilitation of genetic counseling for family planning and cascade testing of relatives at risk.
Barington M, Balslev-Harder M, Krag T
… +5 more, van Overeem Hansen T, Wulff CB, Lausten-Thomsen U, Hjortshøj TD, Østergaard E
Am J Med Genet A
· 2026 Jun · PMID 41568526
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Congenital myopathy-14 (CMYO14) is an ultrarare autosomal recessive disorder caused by biallelic variants in MYL1, with only four patients reported to date. We describe what is likely the fifth reported patient, a neonat...Congenital myopathy-14 (CMYO14) is an ultrarare autosomal recessive disorder caused by biallelic variants in MYL1, with only four patients reported to date. We describe what is likely the fifth reported patient, a neonate with severe hypotonia, respiratory insufficiency, and skeletal anomalies showing distinct histological changes of skeletal muscle consistent with all previously described patients. The patient carried a novel homozygous intron variant (c.479-25T>C, p.(?)) in MYL1. RNA analysis of patient muscle demonstrated aberrant splicing, with inclusion of 19 bp from intron 4 in most transcripts, resulting in a frameshift and premature stop codon, and in-frame skipping of exons 4-5 in a minority of transcripts encompassing functional domains. In addition to core CMYO14 features, the patient presented with craniofacial anomalies not previously described. This case broadens the genotypic and phenotypic spectrum of MYL1-related disease and underscores the diagnostic importance of intron variants, highlighting the value of combining in silico splice prediction with functional RNA analyses.
Draaisma JMT, Reintjes W, Leenders E
… +10 more, Draaisma F, Burgers M, Kleimeier L, Tartaglia M, Klaassens M, Becks R, Renes S, Wingbermühle E, Voermans NC, van Alfen N
Am J Med Genet A
· 2026 Jun · PMID 41560462
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Noonan syndrome (NS) and the clinically related Noonan syndrome with multiple lentigines (NSML) belong to the group of RASopathies. Although pain is not mentioned as a characteristic feature, it has recently been reporte...Noonan syndrome (NS) and the clinically related Noonan syndrome with multiple lentigines (NSML) belong to the group of RASopathies. Although pain is not mentioned as a characteristic feature, it has recently been reported as a clinically significant problem. This pain is likely multifactorial in origin, with a significant contribution from neuropathic mechanisms. Patients with NS also have a high chance of having multifocally enlarged nerves, and sometimes show clinical features of neuropathy. The relationship between these nerve findings, pain, health-related quality of life and neurological symptoms remains unclear. This case series aims to provide more insight into the perceived health-related quality of life and neurological symptoms in nine adults with NS or NSML who reported neuropathic pain and had enlarged nerves. Features of some of these patients were already reported in an earlier article. The perceived health-related quality of life was markedly below average. All patients reported somatosensory symptoms consistent with peripheral neuropathy. Six of nine patients reported muscle weakness. Sensory testing was abnormal in five patients, but muscle strength was normal in all patients. Electrodiagnostic testing was consistent with peroneal neuropathy in one patient, muscle and nerve ultrasound imaging confirmed neuromuscular involvement in five of the six patients who reported muscle weakness. No muscle ultrasound imaging was performed in the sixth patient. This study thus shows that adults with NS and NSML with neuropathic pain and enlarged nerves have a significantly impaired perceived health-related quality of life with a variable clinical neurologic phenotype.
Hickey F, Wolter-Warmerdam K, Maastricht L
… +2 more, Daniels D, Kelminson K
Am J Med Genet A
· 2026 Jun · PMID 41560456
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The pediatric Down syndrome (DS) clinic model improves medical care access and treatment; however, evidence-based outcomes of this model implementing routine screening are not well documented. Our goal was to evaluate th...The pediatric Down syndrome (DS) clinic model improves medical care access and treatment; however, evidence-based outcomes of this model implementing routine screening are not well documented. Our goal was to evaluate the impact of the pediatric DS clinic on the identification of children with DS and celiac disease using a large patient population. This is a retrospective review of a large cohort of children with DS ages 3-22 years (total = 4158; 2011-2024 Sie Center for DS [SCDS] patients = 2164; 2011-2024 Children's Hospital Colorado [CHCO] patients with DS not seen at SCDS = 924; 1998-2010 CHCO patients with DS receiving care at CHCO before the SCDS = 1070) at a large pediatric hospital. Symptoms present, type and frequency of testing completed, and other co-occurring conditions were reviewed. The pediatric DS clinic model using routine screening significantly increased the identification of celiac disease (7.4%, n = 160/2164 vs. 2.4% and 2.8%) with the majority identified by routine screening rather than current American Academy of Pediatrics (AAP) DS Guidelines' recommendations. Impact of repeat screenings and co-occurring condition risk ratios is reported. The pediatric DS clinic model implementing routine screening improves patient identification for celiac disease. Our results should be considered when updating celiac disease testing recommendations in the AAP DS Guidelines for this unique population.
Canales CY, Shields K, Choates M
… +4 more, Hillman P, Farach L, Wittman T, Leal K
Am J Med Genet A
· 2026 May · PMID 41556137
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Genetic conditions suspected in children often require genetic testing for accurate diagnoses, but testing remains costly. Case management teams review genetic test requests to improve access for patients while reducing...Genetic conditions suspected in children often require genetic testing for accurate diagnoses, but testing remains costly. Case management teams review genetic test requests to improve access for patients while reducing the financial burden for medical institutions. Limited data exist on the diagnostic yields of genetic testing in the inpatient versus outpatient setting and the impact to care denial of inpatient genetic testing may pose. This study investigates diagnostic yields between patients approved for versus denied inpatient genetic testing and its impact to care. One thousand and fifty-two charts of children admitted inpatient who received a genetic consult between July 2018 and June 2023 were reviewed; charts of children that followed up at the outpatient genetics clinic after inpatient discharge were additionally reviewed. Collected data included recommendations, completion, and results of genetic testing, and management recommendations based on a diagnosis. Statistical analysis assessed differences between the groups. Private insurance holders and patients with no prematurity history were less likely to be approved for inpatient genetic testing. The outpatient group had nearly twice the diagnostic yield and management recommendations did not differ between the groups. Inclusion of genetic providers in the review of inpatient genetic testing requests should be considered to improve outcomes.
Dong Y, Xiao X, Li S
… +4 more, Jia X, Sun W, Zhang Q, Yi Z
Am J Med Genet A
· 2026 Jun · PMID 41555764
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Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), caused by FOXL2 variants, has been divided into two subtypes by eyelid abnormalities with (BPES-I) or without (BPES-II) primary ovarian insufficiency (POI). Th...Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), caused by FOXL2 variants, has been divided into two subtypes by eyelid abnormalities with (BPES-I) or without (BPES-II) primary ovarian insufficiency (POI). This study investigated the genetic and phenotypic characteristics of FOXL2-associated BPES and their genotype-phenotype correlations. FOXL2 variants were identified by in-house next-generation sequencing and compared with public databases. Clinical features were also summarized. Eleven FOXL2 variants, including four novel, were detected in 11 families from our cohort. Based on literature, 273 FOXL2 pathogenic/likely pathogenic variants were reviewed in 650 patients from 548 families. Nearly half (47.6%, 130/273) of the variants were truncation. The most frequent (24.0%, 132/549) variant was p.A225_A234dup. In the polyalanine tract, variants leading to the deletion of 1-10 or expansion/insertion of 2 alanine residues were likely benign, whereas variants causing the expansion/insertion of 10-15 alanine residues were pathogenic. The proportion of truncation variants was significantly higher in patients with BPES-I (73.8%, 48/65) than in those with BPES-II (19.6%, 19/97). In conclusion, the pathogenicity of in-frame variants within the polyalanine tract was associated with the number of polyalanine residues. Truncation variants were frequently linked to the severe phenotype (BPES-I), highlighting their potential value in clinical diagnosis and patient management, particularly for preventing or treating POI.
Bernhardt I, Stabej PLQ, Hart C
… +7 more, De Hora M, Hulley S, Anderson M, Leitch HG, Lemonde H, Ryder B, Davison J
Am J Med Genet A
· 2026 Jun · PMID 41549939
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Cytosolic phosphoenoylpyruvate carboxykinase (PEPCK-C) is an essential, rate-limiting enzyme in the gluconeogenesis pathway. PEPCK-C deficiency presents with hypoglycaemia, hyperlactataemia and hepatopathy, and was first...Cytosolic phosphoenoylpyruvate carboxykinase (PEPCK-C) is an essential, rate-limiting enzyme in the gluconeogenesis pathway. PEPCK-C deficiency presents with hypoglycaemia, hyperlactataemia and hepatopathy, and was first reported in association with bi-allelic PCK1 variants in 2014. A Finnish cohort with a common homozygous variant (c.925G>A, p.(Gly309Arg)) is well-described, but few other genotypes are reported. Five non-Finnish probands with PEPCK-C deficiency with novel genotypes are presented. All five presented with hypoglycaemia (hypoketotic in three), lactic acidosis, and elevated transaminases. Age at presentation was newborn to 3 years. Two presented with hypoglycaemic seizures after overnight fasting during intercurrent infection. Prominent renal manifestations were noted in two, including proximal tubulopathy with bicarbonate wasting, and acute renal failure, respectively, with markedly elevated plasma glutamine in both. Urine organic acid analysis identified elevated lactate, dicarboxylic aciduria, and tricarboxylic acid cycle metabolites, especially fumarate which was detected in 3/5. PCK1 genotypes included homozygous missense variants c.1211C>T, p.(Ser404Leu) and c.265G>A, p.(Glu89Lys), or compound heterozygous variants including c.824del, p.(Gly275Valfs21); c.496G>A, p.(Val166Met); c.961 + 2 T>C; c.204del, p.(Leu69), and c.728A>G p.(Lys243Arg). A severe phenotype with failure to thrive, short fasting tolerance, liver dysfunction, and tubulopathy was noted in one individual harboring compound heterozygous splicing and nonsense variants. Evidence from in silico analyses and the specific phenotype supported the pathogenicity of novel missense variants. These patients reinforce the recognizable presentation of PEPCK-C deficiency while highlighting renal manifestations and expanding the genotypic spectrum.
Am J Med Genet A
· 2026 May · PMID 41549937
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Alström syndrome (AS) is a rare autosomal-recessive ciliopathy caused by biallelic variants in ALMS1, with an incidence of 1 in 10,000 to 1 in 1,000,000 live births. We report a female diagnosed at age 5 with a previousl...Alström syndrome (AS) is a rare autosomal-recessive ciliopathy caused by biallelic variants in ALMS1, with an incidence of 1 in 10,000 to 1 in 1,000,000 live births. We report a female diagnosed at age 5 with a previously unreported homozygous nonsense variant in ALMS1: c.4740C>G (p.Tyr1580Ter), located in exon 8, a known hotspot for pathogenic variants. The variant aligns with the loss-of-function mechanism seen in most ALMS1-related AS cases and is found within a 15 Mb run of homozygosity, consistent with her history of parental consanguinity. Her clinical picture included progressive hearing loss, dyslipidemia, and worsening hyperglycemia despite lifestyle interventions. Due to accelerated weight gain and declining glycemic control, dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), was initiated. Over 48 weeks, BMI decreased from 190% to 160% of the 95th percentile, with a 0.95 z-score reduction, 1.2% HbA1c decrease into the normal range. This case expands our understanding of the ALMS1 mutational spectrum and provides the first longitudinal report of GLP-1 RA benefit in AS, supporting its consideration as adjunctive therapy and highlighting the need for further study.
Kleinendorst L, Molegraaf MNS, Grange DK
… +2 more, Rinkel RNPM, van Haelst MM
Am J Med Genet A
· 2026 May · PMID 41549877
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Cantú syndrome (CS) is a rare genetic condition caused by pathogenic variants in either ABCC9 or KCNJ8, leading to gain-of-function of K-channels. The main clinical features are hypertrichosis and cardiovascular abnormal...Cantú syndrome (CS) is a rare genetic condition caused by pathogenic variants in either ABCC9 or KCNJ8, leading to gain-of-function of K-channels. The main clinical features are hypertrichosis and cardiovascular abnormalities. This study investigates the voice characteristics in individuals with CS, an aspect that has received little attention in previous research. A total of 18 participants with molecular genetically confirmed CS were recruited, 11 females and 7 males, aged 9-63 years. Voice pitch analysis was conducted using the Voice Tools application, comparing these findings with normative data from healthy individuals. We show that adult females with CS exhibit voice pitches consistently lower than the normative values, particularly below the bottom quartile, suggesting a distinct impact of the underlying gene defect on the adult female voice phenotype. Conversely, adult males with CS show less noticeable deviations in voice pitch compared to healthy males. Children with CS exhibit a voice pitch closer to normative ranges. Adults with CS exhibit a lower voice pitch than healthy controls, especially evident in females. This study highlights the influence of CS on voice pitch, possibly influenced by anatomical abnormalities in CS such as enlarged craniofacial structures and connective tissue alterations affecting vocal fold mass and pliability.