Furuta Y, Rives LC, Burrow TA
… +7 more, Cassini TA, Tinker RJ, Robertson AK, Ezell KM, Hamid R, Cogan JD, Phillips JA
Am J Med Genet A
· 2026 Apr · PMID 42037206
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Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an autosomal recessive mitochondrial defect of long-chain fatty acid β-oxidation, caused by biallelic pathogenic variants in HADHA or HADHB. We report a 2...Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an autosomal recessive mitochondrial defect of long-chain fatty acid β-oxidation, caused by biallelic pathogenic variants in HADHA or HADHB. We report a 22-year-old male with an atypically mild presentation of LCHADD who was referred to the Undiagnosed Diseases Network (UDN). Trio genome sequencing identified a maternally inherited HADHA frameshift pathogenic variant and a paternally inherited noncoding rare HADHA variant. The paternal noncoding variant was predicted by in silico splicing analysis to create a cryptic splice donor site. This was experimentally confirmed to partially perturb splicing, leading to partial disruption of normal splicing and the production of both normal and aberrant transcripts. Transcripts derived from the cryptic donor site were subject to nonsense-mediated decay (NMD). As a result, the proband's cells produced three HADHA transcripts: a truncated maternal transcript that was destroyed by NMD, an abnormally spliced paternal transcript also subject to NMD, and a normally spliced paternal transcript. The presence of residual normally spliced HADHA transcripts from the paternal allele likely contributes to partial preservation of LCHAD enzyme function and provides a plausible explanation for the proband's attenuated clinical phenotype.
Taliercio V, Wilcox A, Cole S
… +9 more, Daboub JF, Morales Moreno JE, Andrews KG, Asaki SY, Pilcher TA, Tristani-Firouzi M, Niu MC, Viskochil D, Hammond B
Am J Med Genet A
· 2026 Apr · PMID 42037199
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Arrhythmias affect approximately half of patients with Costello syndrome (CS, OMIM # 218040), with non-reentrant atrial tachycardia being the most common. This case describes an infant with Costello syndrome carrying the...Arrhythmias affect approximately half of patients with Costello syndrome (CS, OMIM # 218040), with non-reentrant atrial tachycardia being the most common. This case describes an infant with Costello syndrome carrying the pathogenic HRAS c.34G>A (p.G12S) variant who developed early-onset, drug-refractory multifocal atrial tachycardia (MAT). Despite multiple antiarrhythmic therapies, rhythm control remained inadequate until trametinib was initiated, resulting in rapid resolution of MAT and allowing stepwise discontinuation of adjunct antiarrhythmics. Although MAT did not recur after the MEK inhibitor was stopped, the patient subsequently developed hypertrophic cardiomyopathy only after trametinib was discontinued, suggesting a potential disease-modifying cardioprotective effect during active treatment. This case supports MEK inhibition as a targeted antiarrhythmic strategy in Costello syndrome, with benefits that may extend beyond acute rhythm stabilization to include prevention of cardiac hypertrophy. While spontaneous resolution of MAT can occur in Costello syndrome, the rapid and sustained response in this patient strengthens the hypothesis that trametinib exerts a direct antiarrhythmic effect.
Furuta Y, Bloom KN, Vockley J
… +15 more, Grochowsky AR, Agrawal NS, Strickler EW, Owen NN, Gray ET, Perera BLA, Gamazon ER, Rives LC, Chen HC, Liu Q, Hamid R, Cogan JD, Phillips JA, Cassini TA, Schuler BA
Am J Med Genet A
· 2026 Apr · PMID 42037170
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Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is an autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in one of three known genes: ETFA, ETFB, and ETFDH. It can cause multisystem...Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is an autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in one of three known genes: ETFA, ETFB, and ETFDH. It can cause multisystem dysfunction, including cardiomyopathy in severe cases. Ketone supplementation has been reported to be beneficial in a few case reports, but its long-term effectiveness remains unclear. We report an infant with a clinical and biochemical diagnosis of MADD who showed a favorable response to ketone supplementation, with marked improvement in severe cardiac dysfunction and sustained near-normal cardiac function and biochemical profiles over 3.5 years. Although genome sequencing did not identify causative variants, RNA sequencing revealed reduced ETFB transcript levels, and western blot analysis showed decreased ETFB protein levels. This case report illustrates MADD without an identified molecular diagnosis and provides evidence that near-absent ETFB expression is likely responsible for his presentation. These observations can guide further studies investigating the transcriptional regulation of ETFB, thereby elucidating an underappreciated molecular mechanism underlying MADD. Initiating metabolic therapy in patients with clinically suspected MADD, even in the absence of a confirmed molecular diagnosis, can be beneficial as suggested by the clinical and biochemical responses to our therapeutic trial.
Am J Med Genet A
· 2026 Apr · PMID 42037155
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GM3 synthase deficiency (GM3SD), also known as salt and pepper developmental regression syndrome, is a rare autosomal recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in ST3GAL5. It...GM3 synthase deficiency (GM3SD), also known as salt and pepper developmental regression syndrome, is a rare autosomal recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in ST3GAL5. It is characterized by early onset epileptic encephalopathy, severe neurodevelopmental impairment, and sensory deficits. Routine metabolic screening tests are frequently non-specific, which may contribute to delayed diagnosis. We report a Turkish male infant who presented in early infancy with developmental delay and hypotonia, followed by early onset, refractory epilepsy and progressive neurodevelopmental regression. Feeding dysfunction progressed to complete loss of swallowing, necessitating gastrostomy and tracheostomy. Neuroimaging demonstrated diffuse cerebral atrophy and ventriculomegaly, and audiological evaluation revealed bilateral sensorineural hearing loss. Extensive metabolic investigations, including screening for congenital disorders of glycosylation, were non-diagnostic. Whole-exome sequencing identified a novel homozygous frameshift variant in ST3GAL5 (NM_003896.4: c.726_732del, p.(Met242Ilefs*35)), classified as likely pathogenic, confirming the diagnosis of GM3SD. During follow-up, renal calculi and hepatobiliary abnormalities, including biliary sludge, gallstones, and transaminase elevation, were observed. This case highlights the severe neurological course and diagnostic challenges associated with ST3GAL5-related GM3SD and underscores the critical role of comprehensive genetic testing in infants with unexplained epileptic encephalopathy and developmental regression. Although renal and hepatobiliary abnormalities are not considered characteristic features of GM3SD, their occurrence during long-term follow-up emphasizes the need for careful multisystem surveillance in severely affected patients.
Kavčič A, Avsenik J, Writzl K
… +7 more, Stavber L, Bertok S, Debeljak M, Šuštar N, Maver A, Velkavrh M, Šalamon AS
Am J Med Genet A
· 2026 Apr · PMID 42015805
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Due to diverse clinical presentation, tubulinopathy is usually confirmed by genetic analysis. We report a family case series with a novel missense likely pathogenic variant in the TUBB gene. The proband presented with a...Due to diverse clinical presentation, tubulinopathy is usually confirmed by genetic analysis. We report a family case series with a novel missense likely pathogenic variant in the TUBB gene. The proband presented with a severe clinical course, including seizures and global developmental delay starting at 6 months of age. The younger sibling was recognized in the neonatal period due to abnormal cranial ultrasound. Both showed similar brain MRI findings: asymmetrical ventriculomegaly, dysmorphic basal ganglia and asymmetric posterior fossa structures. After identification of the TUBB variant in both siblings and a presumably healthy mother, maternal MRI also demonstrated features consistent with tubulinopathy. This family highlights the critical role of neuroimaging in the diagnosis of tubulinopathies, as characteristic MRI findings can guide genetic interpretation and reclassification of variants. MRI findings enabled reclassification of the TUBB missense variant from variant of uncertain significance to likely pathogenic. The variant showed complete penetrance but markedly variable expressivity, contributing to the broad clinical spectrum associated with TUBB-related disorders.
Niehaus AD, Bonner DE, Carter J
… +24 more, Avello K, Jacob N, Neu MB, Mendez R, Qiao W, Scott SA, Levy RJ, Mattas L, Schymick J, Van Andel M, Muntoni F, Mueller J, Sarkozy A, DiTroia S, O'Leary M, Neale A, O'Donnell-Luria A, Toro C, Wolfe LA, Martinez-Agosto JA, Montgomery SB, Wheeler MT, Bernstein JA, Tise CG
Am J Med Genet A
· 2026 Apr · PMID 42002855
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The vast majority of individuals with autosomal recessive (AR) conditions demonstrate biparental inheritance of the disease-causing alleles; however, de novo variants also contribute to AR disease. This report represents...The vast majority of individuals with autosomal recessive (AR) conditions demonstrate biparental inheritance of the disease-causing alleles; however, de novo variants also contribute to AR disease. This report represents the largest cohort to-date of rare AR conditions in which one of the disease-causing alleles was inherited and one occurred de novo. Clinical and research staff at Stanford University, clinical sites of the Undiagnosed Diseases Network (UDN) and Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium, and a large clinical genetic testing laboratory were contacted to identify cases of an AR diagnosis resulting from an inherited and de novo disease-causing variant in trans. Fifteen cases of AR conditions caused by one inherited and one de novo variant in a gene consistent with the clinical phenotype were identified; all had undergone trio exome or genome sequencing with genetic confirmation of reported relationships. Variants were confirmed to be in trans in eight of the 15 cases. The de novo variant was confirmed (n = 7) or presumed (n = 7) to have arisen on the paternal allele in 14/15 (93%) of cases. Phenotypic and/or molecular evidence of an AR condition should prompt parental segregation analysis to inform diagnosis, recurrence risks, and variant classification. Additional studies are needed to determine the incidence of this phenomenon given the implications for the interpretation of genetic testing and counseling for AR conditions.
Am J Med Genet A
· 2026 Apr · PMID 42002833
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The 46th Annual David W. Smith (DWS) Workshop on Malformations and Morphogenesis returned to the University of Wisconsin-Madison, a site of singular historical resonance for dysmorphology. The program unfolded across six...The 46th Annual David W. Smith (DWS) Workshop on Malformations and Morphogenesis returned to the University of Wisconsin-Madison, a site of singular historical resonance for dysmorphology. The program unfolded across six themes-orofacial morphogenesis, gastrulation and early embryogenesis, tooth morphogenesis/dentition, genitourinary malformations, chromatin remodeling, and cardiovascular disorders-anchored by keynotes and emphasis lectures from Drs. Paul Trainor, Cigall Kadoch, Ophir Klein, Neil Chi, Robert Lipinski, Margaret Adam, and the Founder's Talk by Dr. Marilyn Jones. This narrative report follows the chronological flow of the meeting, providing fuller detail for anchor lectures and synthetic integration of presentations.
Akalın A, Öz V, Pınarbaşı AS
… +3 more, Özalkak Ş, Karaca MS, Yıldırım R
Am J Med Genet A
· 2026 Apr · PMID 41998823
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Grange syndrome is a rare early-onset multisystem disorder characterized by multifocal steno-occlusive arterial disease, bone fragility, congenital cardiac anomalies, skeletal manifestations, and intellectual disability,...Grange syndrome is a rare early-onset multisystem disorder characterized by multifocal steno-occlusive arterial disease, bone fragility, congenital cardiac anomalies, skeletal manifestations, and intellectual disability, caused by biallelic loss-of-function variants in YY1AP1. We report eight affected individuals (six females, two males) from a single consanguineous family. Molecular analysis included exome sequencing in three patients (P1, P5, and P7) and targeted next-generation sequencing in one patient (P8), with Sanger sequencing performed for segregation analysis and parental carrier testing. A novel biallelic YY1AP1 variant (NM_001198903.1: c.2531_2532del; p.E844Gfs*34) was identified in all affected individuals. One patient, a 4-month-old female, harbored an additional novel biallelic pathogenic variant in CLMP (NM_024769.5: c.167dup; p.N56Kfs*2), consistent with a dual molecular diagnosis. The most common presenting feature was multiple fractures, observed in six patients. The mean age at first fracture was 3.6 ± 1.7 years, and the mean baseline bone mineral density (BMD) Z-score was -4.1 ± 1.6. Three patients received intravenous bisphosphonate therapy for at least 2 years, resulting in improvement of mean BMD Z-scores from -4.9 ± 1.9 to -2.4 ± 0.7. This study represents the first Grange syndrome cohort reported from Türkiye and expands the clinical spectrum by demonstrating marked phenotypic variability, multisystem involvement, and potential benefit of bisphosphonate therapy in patients with significant bone fragility.
Mascarenhas S, Gupta Y, K A A
… +5 more, Pande S, Shaikh H, Girisha KM, Radhakrishnan P, Shukla A
Am J Med Genet A
· 2026 Apr · PMID 41992670
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Hennekam lymphangiectasia-lymphedema syndrome (HKLLS) is an autosomal recessive disorder, caused by biallelic variants in CCBE1, FAT4, and ADAMTS3 genes. We herein report a 15-month-old male with peripheral lymphedema, f...Hennekam lymphangiectasia-lymphedema syndrome (HKLLS) is an autosomal recessive disorder, caused by biallelic variants in CCBE1, FAT4, and ADAMTS3 genes. We herein report a 15-month-old male with peripheral lymphedema, facial dysmorphism, camptodactyly and generalized hypotonia. Solo exome sequencing revealed a homozygous splice site variant, c.12479+3A>G in intron 14 of FAT4 (NM_001291303.3). Reverse transcriptase-PCR (RT-PCR) was performed using cDNA isolated from patient-derived fibroblasts, which revealed aberrant splicing. This study provides a report of an additional family with a novel biallelic splice site variant in FAT4 which disrupts the normal splicing of the FAT4 mRNA, leading to aberrant splicing causing a milder form of HKLLS2.
Colello MJ, Myers AY, Gasho JO
… +4 more, Agulnik M, Kang HP, Williams NL, Zuckerman LM
Am J Med Genet A
· 2026 Apr · PMID 41992553
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Patients with Ollier's Disease (OD) and Maffucci Syndrome (MS) are at risk for fractures, deformities, and limb-length discrepancies (LLDs). This study aims to determine the rate and types of surgery performed on these p...Patients with Ollier's Disease (OD) and Maffucci Syndrome (MS) are at risk for fractures, deformities, and limb-length discrepancies (LLDs). This study aims to determine the rate and types of surgery performed on these patients and evaluate the prevalence of developing a malignancy at a prior surgical site. A survey link was posted to a private online social media support group page specific to OD and MS patients. A total of 125 surveys were obtained from five continents. Two surveys were incomplete, and 123 surveys were evaluated with 109 OD and 14 MS patients. 89% had at least one surgery at a mean age of 9.1 years, with an overall average of 7.6 surgeries. Common surgical indications included lower-extremity LLD and deformity correction, and symptomatic enchondroma resection. 19% developed a chondrosarcoma, and 35% of these occurred at a previous surgical site. Four patients developed metastatic disease, and two had an intramedullary nail placed during a prior procedure. The majority of patients with OD and MS will undergo surgery, require multiple procedures, and may develop a chondrosarcoma at a prior surgical site. Caution should be taken in this at-risk population with special consideration for the type of surgery and implants used.
Ottaviani D, Bacchin R, Pjeçi A
… +8 more, Malaguti MC, Longo C, Sarubbo S, Giometto B, Dzinovic I, Zech M, Di Fonzo A, Monfrini E
Am J Med Genet A
· 2026 Apr · PMID 41978253
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Pathogenic variants in CACNA1C have been associated with cardiac arrhythmias and neurodevelopmental disorders, occasionally accompanied by movement disorders. Here we report the case of a 66-year-old female patient with...Pathogenic variants in CACNA1C have been associated with cardiac arrhythmias and neurodevelopmental disorders, occasionally accompanied by movement disorders. Here we report the case of a 66-year-old female patient with combined dystonia-parkinsonism carrying a pathogenic CACNA1C variant. Neurological examination revealed painful tremulous cervical dystonia, blepharospasm, divergent strabismus, hypomimia, and mild dystonic posturing of left hand, action tremor, and bradykinesia of the upper limbs. Botulinum toxin type A injections provided only partial relief of cervical dystonia, so the patient underwent bilateral Deep Brain Stimulation of Globus Pallidus Internus (GPi-DBS), which resulted in dystonia improvement. Genetic analysis identified an extremely rare heterozygous nonsense variant in the CACNA1C gene (NM_199460.3: c.481C > T; NP_955630.3: p.Arg161*), predicted to introduce a premature stop codon resulting in early protein truncation. Haploinsufficiency is a known disease mechanism for this gene. This variant has previously been reported in two individuals with neurodevelopmental phenotypes. Based on ACMG guidelines, the variant was classified as pathogenic. Our findings suggest that CACNA1C variants may be associated with adult-onset movement disorders, even in the absence of a prior history of neurodevelopmental disease. This case broadens the phenotypic spectrum within CACNA1C-related disorders. GPi-DBS may represent a valuable therapeutic option in selected cases.
Li MH, Coleman DL, Hogan K
… +23 more, Luz D, Bhandari L, Belnap N, Busa T, Coutton C, Dieterich K, Gorokhova S, Hildebrandt C, Logan R, Mariani M, Morleo M, Nigro V, Pappas J, Rabin R, Schoch K, Selicorni A, Shashi V, Spillmann R, Sullivan J, Tardy C, Vergano SAS, Grill B, Baranano K
Am J Med Genet A
· 2026 Apr · PMID 41975654
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HUWE1 (HECT, UBA, and WWE Domain Containing E3 Ubiquitin Protein Ligase1, OMIM 300697), located at Xp11.22, encodes a ubiquitin ligase that is highly conserved across species. Genetic variants in HUWE1 described in multi...HUWE1 (HECT, UBA, and WWE Domain Containing E3 Ubiquitin Protein Ligase1, OMIM 300697), located at Xp11.22, encodes a ubiquitin ligase that is highly conserved across species. Genetic variants in HUWE1 described in multiple independent studies cause X-linked intellectual disability, including in the patients identified by Juberg, Marsidi, and Brooks. This report describes 35 additional cases of individuals with variants in HUWE1 and suggested guidelines for clinical management. Our study includes several female cases, which have not been widely reported previously. Our findings confirm earlier reported clinical features including developmental delay, autism, hypotonia, short stature, and dysmorphic facial features as well as additional multisystemic findings. Intrauterine growth restriction (IUGR) and feeding difficulties were common in the neonatal period. It is notable that nearly all females had de novo variants, and males had de novo or inherited variants from clinically unaffected carrier mothers. Three genetic hotspots were identified in evolutionarily conserved regions of HUWE1 that have clinical impact. This report provides additional characterization of the spectrum of HUWE1-related neurodevelopmental disorder (HNDD).
George AM, Duki BT, Katz ZS
… +9 more, Viswanathan A, MacFarland SP, Hathaway ER, Monahan C, Morris J, Trout KL, Krantz SM, Ganguly A, Kalish JM
Am J Med Genet A
· 2026 Apr · PMID 41968606
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WAGR spectrum disorder (WAGRSD) is an ultra-rare congenital disorder caused by heterozygous deletion of chromosome 11p13. While classically associated with Wilms tumor, Aniridia, Genitourinary anomalies, and a Range of d...WAGR spectrum disorder (WAGRSD) is an ultra-rare congenital disorder caused by heterozygous deletion of chromosome 11p13. While classically associated with Wilms tumor, Aniridia, Genitourinary anomalies, and a Range of developmental delays, accurate delineation of the deletion is critical for prognosis because the phenotypic spectrum extends well beyond this tetrad. To improve diagnostic resolution, we developed and validated a high-density custom CGH-SNP array for precise breakpoint mapping of 11p13. We present a molecularly confirmed cohort of 23 new patients and integrate these with 91 published cases, forming the largest combined cohort to date (N = 114) with detailed genotype-phenotype information. Key findings include: (1) the custom array provided superior genomic resolution compared to standard clinical arrays; (2) seven patients (6.1%) were found to have a dual diagnosis of WAGRSD and Potocki-Shaffer syndrome (PSS)-a contiguous-gene syndrome characterized by multiple osteochondromas that requires distinct surveillance; (3) in 42 patients with fully defined deletions (n = 42, 38% of the cohort), no statistically significant association was observed between deletion of LMO2 (or other candidate genes) and Wilms tumor risk; and (4) phenotypic frequencies in this medically validated cohort closely aligned with prior caregiver-reported registry data, validating patient-driven registries as a reliable resource for rare disease research. Together, these findings underscore the necessity of high-resolution genomic testing to guide counseling, refine anticipatory management-including screening for PSS-related complications-and expand the phenotypic understanding of 11p13 deletion disorders.
Ting SL, Bassett J, Meyer J
… +8 more, Anderson M, Bowron A, Weber A, Wu THY, Mitchell R, Robinson R, Morris AAM, Stepien KM
Am J Med Genet A
· 2026 Apr · PMID 41968386
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Fumarase deficiency (FMRD) is a rare autosomal recessive disorder caused by fumarate hydratase (FH) deficiency, with variable presentation from severe early-onset encephalopathy to mild cognitive impairment. Heterozygous...Fumarase deficiency (FMRD) is a rare autosomal recessive disorder caused by fumarate hydratase (FH) deficiency, with variable presentation from severe early-onset encephalopathy to mild cognitive impairment. Heterozygous carriers of some variants are predisposed to hereditary leiomyomatosis and renal cell carcinoma (HLRCC). We retrospectively reviewed clinical, biochemical, and molecular data from patients with confirmed or suspected FMRD across three metabolic centers in Northern England. Ten patients (seven females, three males) from seven families were identified, with a median diagnostic age of 5 years (range: 1 day-16 years). All had developmental delay and learning difficulties of varying severity. Elevated urinary fumarate was found in 7/10 patients but was inconsistent on repeat analysis. Five patients had neutropenia, and four had abnormal neuroimaging findings. Biallelic FH variants were identified in nine patients, comprising five variants: four missense and one in-frame duplication. The c.410C>T variant accounted for 44% of mutant alleles, and three patients were homozygous for c.1431_1433dupAAA p.(Lys477dup). Renal lesions were detected in two heterozygous fathers. Elevated urinary fumarate was not a consistent feature in some patients. The c.1431_1433dupAAA variant was identified in the homozygous state in patients with mild intellectual disability and features overlapping with FMRD. Our findings suggest that all variants identified in FMRD patients require independent clinical evaluation for HLRCC association.
Rasmussen CA, Izdebski M, Paltzer A
… +3 more, Hickey R, Pollard L, Baker J
Am J Med Genet A
· 2026 Apr · PMID 41968348
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Since 2015, Ann and Robert H. Lurie Children's Hospital has performed diagnostic testing for infants who screen positive for mucopolysaccharidosis type II (MPS II) on the Illinois newborn screen. Preliminary diagnostic t...Since 2015, Ann and Robert H. Lurie Children's Hospital has performed diagnostic testing for infants who screen positive for mucopolysaccharidosis type II (MPS II) on the Illinois newborn screen. Preliminary diagnostic testing includes measurement of plasma iduronate-2-sulfatase enzyme activity and urinary glycosaminoglycan analysis, followed by sequencing of the IDS gene. These diagnostic studies rule out or confirm a diagnosis of MPS II for most cases. However, occasionally, a diagnosis of MPS II remains uncertain following initial diagnostic studies. In this case series, we describe our experience with uncertain diagnoses of MPS II, outline our approach to confirming a diagnosis of MPS II, and emphasize the diagnostic utility of fractionated urine glycosaminoglycans analysis.
Am J Med Genet A
· 2026 Apr · PMID 41964124
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Osteopathia striata with cranial sclerosis (OSCS) is a rare X-linked dominant genetic disorder mediated by variants in the AMER1 gene, characterized primarily by generalized skeletal sclerosis and striated changes. Howev...Osteopathia striata with cranial sclerosis (OSCS) is a rare X-linked dominant genetic disorder mediated by variants in the AMER1 gene, characterized primarily by generalized skeletal sclerosis and striated changes. However, research on its craniofacial phenotypes has long been fragmented, lacking systematic pedigree construction and basis for precise management. This study integrates a 16-year follow-up patient carrying a novel AMER1 frameshift variant (c.966delT; p.Phe322Leufs*3) with 66 literature-confirmed patients, and systematically analyzes craniofacial phenotypic characteristics and genetic associations using Spearman correlation analysis, two-step clustering, and gene function prediction. The results show that orofacial clefts have the highest incidence (72%), with synergistic associations between retained deciduous teeth and impacted permanent teeth; two-step clustering identified four heterogeneous "genetic abnormality-phenotype" subtypes, with DNA/protein functional status as the core factor; it confirms that c.966delT is a pathogenic de novo variant, mediating Wnt pathway abnormalities as the core mechanism of phenotypes, and proposes a multidisciplinary management strategy. This study is the first to establish a quantitative pedigree and subtype classification for OSCS craniofacial phenotypes, deepening the understanding of molecular mechanisms and providing key basis for precise diagnosis, stratified intervention, and prognosis improvement.
Harrington CN, Kohl E, Gilitwala Z
… +5 more, Teng J, Siegel DH, Charville GW, Steffner RJ, Stevenson DA
Am J Med Genet A
· 2026 Apr · PMID 41964119
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CBL syndrome is a RASopathy with phenotypic variability including neurodevelopmental differences, cardiac defects, growth delay, dysmorphic and cutaneous findings, hematologic, immunologic, and vascular manifestations, a...CBL syndrome is a RASopathy with phenotypic variability including neurodevelopmental differences, cardiac defects, growth delay, dysmorphic and cutaneous findings, hematologic, immunologic, and vascular manifestations, and predisposition to juvenile myelomonocytic leukemia (JMML). We present a patient with a germline likely pathogenic variant in CBL with ten café au lait macules and a recurrent granular cell tumor. Granular cell tumors have not been described in this condition. This case broadens the recognized clinical spectrum of CBL syndrome and challenges the existing genetic testing approach for patients with greater than six café au lait macules.
Artinger KB, Fantauzzo KA, Merrill AE
… +4 more, Stottmann RW, Taneyhill LA, Van Otterloo E, Harris MP
Am J Med Genet A
· 2026 Apr · PMID 41956963
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The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 48th Annual Meeting at the University of Minnesota in Minneapolis on September 29-October 1, 2025. On the first day of the meeting, Drs. Ti...The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 48th Annual Meeting at the University of Minnesota in Minneapolis on September 29-October 1, 2025. On the first day of the meeting, Drs. Timothy Cox and Jennifer Fish were honored with Excellence in Craniofacial Research Awards for their exceptional contributions to the field of craniofacial biology. The following 2 days of the meeting featured five sessions that highlighted new discoveries in human genetics, systems biology of craniofacial development and disease, evolutionary connections, signaling mechanisms, and a special session on clinical and patient perspectives. The meeting also featured workshops on scientific writing and the role of artificial intelligence in advancing research and care. A poster session facilitated dynamic and insightful interactions among the 113 attendees, who represented diverse career stages and research backgrounds in developmental biology and genetics, further strengthening the SCGDB community.
Zechi-Ceide RM, Segarra VCD, Vendramini-Pittoli S
… +8 more, Serigatto HR, Virmond L, da Cunha Palhares HM, Jehee F, Krepischi ACV, Rosenberg C, Grangeiro CHP, Kokitsu-Nakata NM
Am J Med Genet A
· 2026 Apr · PMID 41952423
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The transformation/transcription domain-associated protein (TRRAP) gene encodes a large multidomain protein, a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family. TRRAP is a component of the histone...The transformation/transcription domain-associated protein (TRRAP) gene encodes a large multidomain protein, a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family. TRRAP is a component of the histone acetyltransferase (HAT) complex, and it plays an important role in gene transcription, DNA repair, and cell-cycle regulation. Heterozygous missense variants in the TRRAP gene have been associated with a multiple system condition known as developmental delay with or without dysmorphic facies and autism (DEDDFA; OMIM #618454), hearing loss, and different types of cancer. Strong genotype-phenotype correlation has been observed in DEDDFA, where missense variants located in the clustering between residues 1031-1159 result in more pronounced facial anomalies associated with a variable degree of intellectual disability. Here, we report two Brazilian females with syndromic orofacial cleft, presenting very similar atypical facial phenotypes and multisystem anomalies. Both had a severe phenotype with global developmental delay, ranging from moderate to severe, and one of them had a severe behavior disorder associated with non-verbal autism while the other had inguinal cancer. Next-generation sequencing showed that both displayed heterozygous missense variants in the TRRAP gene, clustering at the 1031-1159 amino acid residues. These cases reinforce the genotype-phenotype correlation of variants in the TRRAP gene with a possible new domain in the cluster 1031-1159.