Molecular Syndromology[JOURNAL]
Sun
200 papers
Double Genetic Diagnosis Involving MECP2 and EPHB4 in a Child with Neurodevelopmental Delay and Vascular Anomalies: A Case Report.
Sanri A, Mutlu MB
Mol Syndromol · 2025 Oct · PMID 41409310 · Full text
BACKGROUND: Double genetic diagnoses are increasingly identified with the advent of genome-wide sequencing techniques. While mutations are associated with Rett syndrome and mutations with vascular malformation syndrome...
BACKGROUND: Double genetic diagnoses are increasingly identified with the advent of genome-wide sequencing techniques. While mutations are associated with Rett syndrome and mutations with vascular malformation syndromes, their co-occurrence has not been previously described. CASE PRESENTATION: We describe an 8-year-and-2-month-old girl presenting with global developmental delay, autism spectrum disorder, and stereotypic behaviors, along with multiple well-demarcated cutaneous vascular lesions. Although she had no clinical seizures, electroencephalogram revealed epileptiform discharges. Physical examination showed dysmorphic features and vascular anomalies, including telangiectatic pink-to-red macular vascular lesions. Whole exome sequencing (WES) identified two de novo heterozygous pathogenic variants: a missense mutation in (c.433C>T; p.Arg145Cys), a gene classically implicated in Rett syndrome, and a nonsense mutation in (c.1093C>T; p.Arg365Ter), which has been previously associated with capillary malformation-arteriovenous malformation syndrome type 2. The neurodevelopmental findings, while consistent with the broader spectrum of -related disorders, along with coexisting vascular anomalies, were best accounted for by a dual genetic diagnosis involving both and CONCLUSION: This case underscores the diagnostic value of considering dual genetic diagnoses in patients with complex phenotypes and highlights the role of WES in uncovering multilocus variation, thereby expanding the known phenotypic spectrum associated with and mutations.
Blended Phenotypes in Siblings: Dual Diagnoses of Nicolaides-Baraitser and Craniosynostosis Syndromes.
Bizzari S, Mehawej C, Chouery E … +5 more , Nair P, Corbani S, Lefranc G, El-Hayek S, Megarbane A
Mol Syndromol · 2025 Oct · PMID 41409309 · Full text
INTRODUCTION: Neurodevelopmental and multiple malformation disorders spanning large phenotypic series can often lead to obscure diagnoses in the clinic. Blended phenotypes from multiple etiologies can compound this issue...
INTRODUCTION: Neurodevelopmental and multiple malformation disorders spanning large phenotypic series can often lead to obscure diagnoses in the clinic. Blended phenotypes from multiple etiologies can compound this issue. We present a rare familial case of two siblings with Nicolaides-Baraitser syndrome (NCBRS) complicated by an initial diagnosis of syndromic craniosynostosis in one of the patients. CASE PRESENTATION: Whole exome sequencing (WES) was performed for the affected siblings using the Agilent SureSelect kit and Illumina HiSeq 2500 system, followed by GATK variant calling and in-house annotation. Sanger sequencing was used to validate candidate variants in all immediate family members. A pathogenic de novo variant in (p.Gln646Ter), consistent with craniosynostosis type 3 (CRS3), was identified in the proband, along with a novel likely pathogenic variant in (p.Ile833Phe) involved in NCBRS. The latter was also detected in the sister and is thus suspected to have arisen through germline mosaicism. Various overlapping phenotypic manifestations complicated clinical diagnosis. CONCLUSION: This case expands the molecular and clinical spectrum of NCBRS and CRS3 and underscores the utility of trio-based WES in detecting blended phenotypes of disorders with growing phenotypic spectrums. Paternal germline mosaicism may underlie high recurrence and inform reproductive counseling.
Two Unrelated Witteveen-Kolk Syndrome Patients Presenting with Unusual Clinical Features: Dual Diagnosis and Atypical Rare Manifestation.
Yilmaz M, Ozden A, Doneray H … +3 more , Bahadır O, Apuhan T, Turkyilmaz A
Mol Syndromol · 2025 Nov · PMID 41409308 · Full text
INTRODUCTION: Witteveen-Kolk syndrome (WITKOS, OMIM 613406) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function variants in the gene or microdeletions involving at 15q24. We...
INTRODUCTION: Witteveen-Kolk syndrome (WITKOS, OMIM 613406) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function variants in the gene or microdeletions involving at 15q24. We aimed to present new clinical and genetic findings of 2 patients diagnosed with WITKOS. CASE PRESENTATION: This study presents 2 cases: patient 1 had genomic variations caused by a multilocus disease, including pathogenic variations in the gene and paternal mosaic uniparental disomy 11 (UPD(11)p), and showed syndromic symptoms. Patient 2 was followed up with a preliminary diagnosis of hypogonadotropic hypogonadism (HH) and a new de novo pathogenic variation in the gene. CONCLUSIONS: These findings expand the phenotypic spectrum associated with variants and highlight the importance of comprehensive genetic testing in atypical presentations of rare diseases. The inclusion of in HH gene panels may aid molecular diagnosis in cases without apparent syndromic findings. This study contributes to the understanding of the phenotypic and genotypic heterogeneity of WITKOS.
Arg339Gln Is a Recurrent Variant in Rare Combined Oxidative Phosphorylation Deficiency 4: A New Patient with Biallelic Gene Variant.
Tekmenuray-Unal A, Tas M, Kangin M … +1 more , Bozaci AE
Mol Syndromol · 2025 Nov · PMID 41409307 · Full text
INTRODUCTION: Combined oxidative phosphorylation deficiency 4 (COXPD4, OMIM #610678) is a very rare mitochondrial disorder caused by biallelic variants in gene. The condition is characterized by microcephaly, severe ear...
INTRODUCTION: Combined oxidative phosphorylation deficiency 4 (COXPD4, OMIM #610678) is a very rare mitochondrial disorder caused by biallelic variants in gene. The condition is characterized by microcephaly, severe early-onset lactic acidosis, and progressive, often fatal, infantile encephalopathy. To date, only 8 patients with biallelic variants have been reported. CASE PRESENTATION: We present a case of a female infant with microcephaly who died from severe lactic acidosis at 7 months of age. Genetic analysis revealed homozygous c.1016G>A (p.Arg339Gln) variant in the gene, which has previously been reported in three other COXPD4 cases. This is the fourth publication describing the same variant in this rare disorder, suggesting that it is a recurrent variant in COXPD4 patients. CONCLUSION: Arg339Gln variant was found in all patients from Turkey and is considered a potential founder mutation. This report aims to contribute to the phenotypic spectrum of COXPD4, explore the frequency and clinical presentation of the reported variants, enhance the understanding of genotype-phenotype correlations, and raise awareness of rare mitochondrial disorders.
A Novel Frameshift Variant Presenting with Autism and Psychiatric Features: Intrafamilial Phenotypic Variation - A Case Report.
Özcan S, Yeter B
Mol Syndromol · 2025 Oct · PMID 41409306 · Full text
INTRODUCTION: Pathogenic variants in the gene, encoding a lysine methyltransferase involved in chromatin remodeling, have been associated with intellectual disability, autism spectrum disorder, and various craniofacial...
INTRODUCTION: Pathogenic variants in the gene, encoding a lysine methyltransferase involved in chromatin remodeling, have been associated with intellectual disability, autism spectrum disorder, and various craniofacial features. However, the detailed genotype-phenotype correlations have yet to be fully elucidated. CASE PRESENTATION: We report a four-year-old male patient who presented with developmental delay, impaired social interaction, repetitive behaviors, and language delay. Whole-exome sequencing identified a novel heterozygous frameshift variant in (c.618del; p.Glu206Aspfs*7). Segregation analysis revealed that the patient's father also carried the same variant and exhibited intellectual disability and obsessive-compulsive disorder. CONCLUSION: By presenting a novel variant alongside an atypical adult neuropsychiatric presentation, this report broadens both the variant and phenotypic spectrum of haploinsufficiency. It further underscores the potential for neurobehavioral manifestations to extend beyond childhood, advocating for sustained clinical surveillance and age-spanning neuropsychiatric assessment.
One-Carbon Metabolism and Midbrain Dopaminergic Cells in Lesch-Nyhan Disease.
Alsuwaidi S, Ernst C
Mol Syndromol · 2025 Nov · PMID 41409305 · Full text
BACKGROUND: Lesch-Nyhan disease (LND) is characterized by severe motor problems, self-injury, and gout. LND is caused by loss of function of HPRT which functions to salvage purine nucleotides, but the link between purine...
BACKGROUND: Lesch-Nyhan disease (LND) is characterized by severe motor problems, self-injury, and gout. LND is caused by loss of function of HPRT which functions to salvage purine nucleotides, but the link between purine recycling and the neurological phenotypes remains unknown. One-carbon metabolism (OCM) is the utilization of single-carbon units for important cellular pathways such as de novo purine synthesis, the methionine cycle, and the transsulfuration pathway. Since purine salvage is lost in LND and one-carbon groups are required for de novo purine synthesis, there is an obligate need to re-route one-carbon flux in LND. Midbrain dopaminergic neurons have been associated with LND and may represent an important intersection point for OCM and LND. SUMMARY: In this review, we analyze the relationships between HPRT loss, OCM, and the unique metabolic features of midbrain dopaminergic cells. Our hope is to better understand how changes to metabolic flux in OCM might affect midbrain dopaminergic cells and ultimately lead to the neurological phenotypes of LND. KEY MESSAGES: OCM provides important components for different processes and pathways including de novo purine synthesis, methionine cycle, transsulfuration pathway, and polyamine synthesis. Changes in flux toward de novo purine synthesis in LND may affect these interconnected processes and have potential effects on dopaminergic cells as discussed in this review.
Genetic Syndromes Including Intellectual Disability and Different Cancer Types.
Ünsel-Bolat G, Dutar E, Bolat H
Mol Syndromol · 2025 Oct · PMID 41409304 · Full text
BACKGROUND: The aim of this study was to determine genetic syndromes including both cancers and intellectual disabilities, specific cancer types accompanying intellectual disabilities. SUMMARY: We obtained the data from...
BACKGROUND: The aim of this study was to determine genetic syndromes including both cancers and intellectual disabilities, specific cancer types accompanying intellectual disabilities. SUMMARY: We obtained the data from the clinical synopsis of the syndromes available in the OMIM database (https://www.omim.org/). In the first step, we detected 794 syndromes using different terms of intellectual disabilities and cancers. In the second step, we investigated the clinical synopsis of each syndrome in detail. Of these, we included 99 syndromes in which both intellectual disability and any type of cancer were presented. In the third step, we collected following data of these 99 syndromes: OMIM number, gene and location, syndrome/protein, tumor/neoplasia, inheritance, growth, head/neck, respiratory, cardiovascular, abdomen, genitourinary, skeletal, skin/nails/hair, neurologic, endocrine features, immunology, prenatal manifestations, laboratory abnormalities, and other system findings. KEY MESSAGES: The most common cancer types among these 99 syndromes are listed in percentage. Since individuals with intellectual disabilities have difficulty expressing themselves and understanding the symptoms of the disease, the diagnosis of diseases in these people is late and their treatment becomes difficult. We suggest that genetic tests to be performed in intellectual disability are important for early diagnosis, follow-up, and treatment of accompanying cancers. We especially emphasize the importance of leukemia, brain tumors, and tumors of embryonal origin in individuals with intellectual disability.
Phenotypic Divergence in Siblings with the Same Genotype: Diffuse Dermal Melanocytosis in Infantile-Onset Galactosialidosis.
Gürbüz BB, Özalp Ö
Mol Syndromol · 2025 Oct · PMID 41409303 · Full text
BACKGROUND: Galactosialidosis (GS) is an ultra-rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the CTSA gene. The resulting deficiency of protective protein/cathepsin A leads to reduc...
BACKGROUND: Galactosialidosis (GS) is an ultra-rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the CTSA gene. The resulting deficiency of protective protein/cathepsin A leads to reduced β-galactosidase and α-neuraminidase activity, causing multisystem involvement. While typical features include dysmorphic facies, organomegaly, skeletal dysplasia, and neurological impairment, dermatologic manifestations remain poorly characterized. CASE PRESENTATION: We report a 9-month-old girl presenting with hepatosplenomegaly and diffuse dermal melanocytosis. Her history included nonimmune hydrops fetalis, congenital cataract, developmental delay, and recurrent respiratory infections. Clinical and radiological evaluation revealed coarse facial features, dysostosis multiplex, and periventricular white matter changes. Enzyme assay demonstrated markedly reduced β-galactosidase activity. Genetic testing identified a homozygous CTSA c.359T>C (p.Ile120Thr) variant, classified as likely pathogenic. Family screening revealed her 10-year-old brother carried the same variant in homozygosity. He exhibited milder features, including developmental delay, hearing loss, and skeletal abnormalities without cutaneous involvement or organomegaly. Enzymatic deficiency was confirmed in both siblings. CONCLUSION: This report highlights diffuse dermal melanocytosis as a possible novel cutaneous marker of GS, potentially aiding early recognition. It also illustrates intrafamilial phenotypic variability despite identical genotypes. Our findings underscore the importance of dermatologic clues in the diagnostic workup of lysosomal storage disorders and advocate for family-based genetic screening to identify asymptomatic or mildly affected individuals.
A Candidate Gene for Cerebro-Oculo-Nasal Syndrome: A Zinc-Finger Gene Located at Xq28.
Hazan F, Yılmaz Uzman C, Emecen DA … +7 more , Yılmazer MM, Öztürk T, Bilen MM, Hüvez A, İlhan R, Genel F, Ballar P
Mol Syndromol · 2025 Nov · PMID 41404552 · Full text
INTRODUCTION: Cerebro-oculo-nasal syndrome (CONS) is characterized by ocular alterations ranging from anophthalmia/microphthalmia to normal eyes, structural anomalies of the central nervous system, and proboscis-like nar...
INTRODUCTION: Cerebro-oculo-nasal syndrome (CONS) is characterized by ocular alterations ranging from anophthalmia/microphthalmia to normal eyes, structural anomalies of the central nervous system, and proboscis-like nares. This syndrome was first described more than 30 years ago, but only 21 patients have been reported to date. CASE PRESENTATION: In the present report, we present a 20-year-old CONS patient who exhibited anophthalmia, microphthalmia, cleft lip-palate, and proboscis-like nares. Exome sequencing (ES) analysis was performed for clinical diagnosis for the index case; her parents were evaluated with Sanger sequence analysis methods in terms of the variation detected in the index case. The ES analysis of the patient identified a novel heterozygous frameshift variant in the gene. This variant was not detected in her parents, whose biological relationship to the patient was confirmed through identity testing. According to the American College of Medical Genetics and Genomics (ACMG) criteria, this novel de novo variant was assessed as likely pathogenic. Peripheral blood mononuclear cells were isolated from peripheral blood of the patient and her parents. Protein was extracted and analyzed by Western blot using antibodies against and GAPDH as control. Western blot analysis detected an ∼80 kDa protein in both the patient and her healthy parents. Additionally, extra bands (∼20-25 kDa) were observed in the patient using the anti- antibody. CONCLUSION: We aimed to evaluate all CONS patients based on their clinical features. Furthermore, we propose that the gene may play a role in the etiology of CONS.
Concomitant Mosaic Turner Syndrome and Congenital Adrenal Hyperplasia in 1 of 3 Patients of Variant-Associated Autism Spectrum Disorder.
Güleç A, Gerik-Celebi HB, Demiral M
Mol Syndromol · 2025 Dec · PMID 41378243 · Full text
INTRODUCTION: X-linked intellectual developmental disorder 99 (XLID99) is a rare neurodevelopmental disorder associated with mutations in the gene. This study reports on 3 patients diagnosed with autism spectrum disorde...
INTRODUCTION: X-linked intellectual developmental disorder 99 (XLID99) is a rare neurodevelopmental disorder associated with mutations in the gene. This study reports on 3 patients diagnosed with autism spectrum disorder (ASD), highlighting novel genetic findings. CASE PRESENTATION: Among the 3 patients, two male siblings exhibited a novel gene missense variant, while the third, a female, presented a unique deletion of the gene alongside adrenal insufficiency and mosaic Turner syndrome. This variant has not been reported in public databases and may influence ASD development. CONCLUSION: This report documents the first instance of a triple diagnosis of XLID99, Turner syndrome, and congenital adrenal hyperplasia. Findings underline the significance of genetic evaluation in ASD for identifying rare and complex diagnoses.
Meckel-Gruber Syndrome due to Homozygous c.16del (p.Leu6SerfsTer15) Variant in the : First Case from Türkiye.
Turan L, Gökpinar Ili E, Doğan M … +2 more , Erenel H, Gezdirici A
Mol Syndromol · 2025 Dec · PMID 41378242 · Full text
INTRODUCTION: Meckel-Gruber syndrome (MKS) is a clinically and genetically heterogeneous ciliopathy characterized by a triad of occipital encephalocele, polycystic kidneys, and postaxial polydactyly. Almost all of them a...
INTRODUCTION: Meckel-Gruber syndrome (MKS) is a clinically and genetically heterogeneous ciliopathy characterized by a triad of occipital encephalocele, polycystic kidneys, and postaxial polydactyly. Almost all of them are lethal in the prenatal or first postnatal periods. It is usually diagnosed clinically with a detailed prenatal ultrasound examination. Variants have been reported in at least 14 different genes. CASE PRESENTATION: We report a male fetus with oligohydramnios, large kidneys with microcysts covering the entire abdomen, postaxial polydactyly of the hands, bilateral pes equinovarus, encephalocele, microphthalmia, short extremities, and a mass lesion under the diaphragm. Termination was recommended to the family due to severe findings. Fetal skin biopsy and parental peripheral blood samples were obtained to investigate the potential pathogenic variants associated with MKS via clinical exome sequencing and Sanger sequencing. CONCLUSION: The fetus was homozygous for the c.16del (p.Leu6SerfsTer15) variant in the (NM_001082538.3), and both parents were heterozygous for the variant. Genetic diagnosis is very important in terms of counseling for subsequent pregnancies. To our knowledge, this is the third Meckel-Gruber case in the literature caused by the , and a novel likely pathogenic variant was detected.
A Biallelic Deletion Underlies Truncus Arteriosus.
Enomoto Y, Naruto T, Mitsui J … +2 more , Ueda H, Kurosawa K
Mol Syndromol · 2025 Dec · PMID 41378241 · Full text
INTRODUCTION: Truncus arteriosus (TA) is a life-threatening cardiovascular anomaly involving a ventricular septal defect and a common ventricular outflow tract. Recently, biallelic variants in have been identified as ca...
INTRODUCTION: Truncus arteriosus (TA) is a life-threatening cardiovascular anomaly involving a ventricular septal defect and a common ventricular outflow tract. Recently, biallelic variants in have been identified as causative for structural heart defects and renal anomalies syndrome (SHDRA, MIM 617478), which includes TA. Approximately 30 patients with SHDRA have been reported, but the genotype-phenotype correlation remains unclear. Founder variants have been identified in patients of East Asian and Ashkenazi Jewish ancestry. CASE PRESENTATION: The male infant, the third child of unrelated Japanese parents, was prenatally diagnosed with TA via detailed ultrasound examination. His older sister also had TA and died at 20 days of age. Despite intensive cardiorespiratory care, the patient passed away at 53 days due to heart failure. Genetic analysis identified a homozygous deletion of exons 6 and 7, resulting from a 7,066-bp deletion with a 1 bp insertion, inherited from heterozygous parents. This deletion is included in the structural variation dataset with an allele frequency of 0.00173 (29/8,380) in ToMMo 8.3K JPN-SV. DISCUSSION: This is the first familial TA caused by a biallelic structural variation in . The 7,066-bp deletion shows a high allele frequency in the Japanese population. These findings support the idea that this deletion may be a significant cause of TA and should therefore be considered alongside the previously known c.1617del variant as a potential causative factor.
Out-of-Frame Transcript and in-Frame Deletion owing to a Novel Splice Mutation of (c.1266+2T>A) in an Adult with Kniest Dysplasia: A Case Report.
Sawamura K, Matsushita M, Okamoto T … +4 more , Mishima K, Sawai H, Kitoh H, Imagama S
Mol Syndromol · 2025 Dec · PMID 41378240 · Full text
INTRODUCTION: Kniest dysplasia is a severe form of type II collagenopathy caused by mutations in collagen II alpha 1 chain () gene. It can be diagnosed in early childhood based on the clinical findings of short stature,...
INTRODUCTION: Kniest dysplasia is a severe form of type II collagenopathy caused by mutations in collagen II alpha 1 chain () gene. It can be diagnosed in early childhood based on the clinical findings of short stature, splayed epiphysis, narrowed joint spaces and platyspondyly associated with maxillofacial, ophthalmological, and otolaryngological complications. Missense mutations and small deletions owing to exon skipping in the triple-helical region of COL2A1 have been reported in most cases of Kniest dysplasia. CASE PRESENTATION: We describe a female patient aged 39 years with difficulty in walking, back pain, and limited movement of the lower extremities. She had experienced neck pain during adolescence; however, it gradually decreased with age. She also showed markedly short stature (-4.37 SD), cleft palate, cataract, retinal detachment, and serous otitis media. Radiographic analyses revealed epiphyseal enlargement of the longitudinal bones, kyphoscoliosis, and flat vertebrae in the thoracolumbar spine. The cervical spinal bodies were fused but not at the age of 19 years. Genetic analysis revealed a novel heterozygous mutation, c.1266+2T>A, in intron 20 of . In silico predictive tools indicated that this mutation was pathological. Exon-trapping assay showed that this splice mutation led to both intron retention and exon skipping in the triple-helical region. These clinical findings and genetic tests confirmed the diagnosis of Kniest dysplasia. DISCUSSION: The diagnosis of Kniest dysplasia is sometimes difficult based on clinical findings in adulthood owing to progressive skeletal changes. The current novel splice mutation in demonstrates both out-of-frame transcript and in-frame deletion in Kniest dysplasia.
Management of Neonatal Severe Hyperparathyroidism due to Homozygous Mutation: Challenges and Literature Insights.
Karakaş H, Aksakal N, Tarçın G … +9 more , Çolakoğlu A, Bayram ME, Velioğlu Haşlak G, Uçar M, Altun İ, Bingöl Aydın D, Turan H, Bayramoğlu E, Evliyaoğlu O
Mol Syndromol · 2025 Dec · PMID 41378239 · Full text
INTRODUCTION: Neonatal severe hyperparathyroidism (NSHPT) is a rare but life-threatening disorder caused by inactivating variants in the calcium-sensing receptor (), resulting in severe hypercalcemia during the neonatal...
INTRODUCTION: Neonatal severe hyperparathyroidism (NSHPT) is a rare but life-threatening disorder caused by inactivating variants in the calcium-sensing receptor (), resulting in severe hypercalcemia during the neonatal period. Infants with NSHPT may present with severe hypercalcemia, hyperparathyroidism, growth retardation, and respiratory distress. If untreated, NSHPT can lead to life-threatening complications. Due to its rarity, few cases have been reported in the literature. CASE PRESENTATION: A 4-day-old girl presented with jaundice, weight loss, and hypercalcemia (16 mg/dL). On physical examination, she appeared dehydrated and hypotonic, and had facial dysmorphisms. Laboratory results revealed markedly elevated parathyroid hormone levels (1,769 pg/mL) and low urinary calcium excretion. Despite initial treatment with hydration and furosemide, her hypercalcemia persisted. Cinacalcet was started but failed to control calcium levels, leading to the need for a subtotal parathyroidectomy at 2.5 months of age. Genetic testing identified a homozygous mutation in the gene (p.Met741LeufsTer24). Postoperatively, the patient developed hypocalcemia due to hungry bone syndrome and later experienced recurrent hypercalcemia, which was managed with pamidronate followed by calcitriol. At 21 months of age, she remains normocalcemic on daily calcitriol. CONCLUSION: This case highlights the challenges in managing NSHPT, especially in cases resistant to medical treatment. Subtotal parathyroidectomy proved essential for controlling hypercalcemia. Continued documentation of NSHPT cases will help improve treatment strategies and outcomes for this rare condition.
EpiSignature Utility for Variant of Uncertain Significance Reclassification in an Apparently Atypical Presentation of -Related Neurodevelopmental Disorder: A Case Report.
Zuelke A, Li R, Taylor C … +2 more , Gilkerson C, Platt D
Mol Syndromol · 2025 Dec · PMID 41378238 · Full text
INTRODUCTION: Current guidelines recommend broad sequencing as a first-tier test for epilepsy, identifying a genetic etiology in 40% of cases. Sequencing subsequently increases the number of patients identified with vari...
INTRODUCTION: Current guidelines recommend broad sequencing as a first-tier test for epilepsy, identifying a genetic etiology in 40% of cases. Sequencing subsequently increases the number of patients identified with variants of uncertain significance (VUSs). Clinicians desire additional investigatory methods to better classify these VUSs. CASE PRESENTATION: The gene (MIM #602869) is associated with a neurodevelopmental condition characterized by intellectual disability and developmental delay, epilepsy, and characteristic facial features. To date, only de novo variants with complete penetrance have been described. We present a 7-year-old female with variant c.669_691dup; p.Gly231Valfs*116, classified as both pathogenic (Laboratory A) and as a VUS (Laboratory B). This patient exhibits an isolated seizure phenotype, and familial studies revealed the proband's father (asymptomatic), paternal uncle (epilepsy), and paternal grandmother (asymptomatic) all carry this variant. Laboratory B theorized the potential for alternative splicing, reducing concerns about pathogenicity. Methylation studies were pursued for more accurate classification and are conclusively negative for the episignature. This, in the context of the variant not segregating with the familial epilepsy phenotype, indicates a benign classification for the c.669_691dup; p.Gly231Valfs*116 variant. CONCLUSION: The number of epilepsy patients with nondiagnostic genetic results requires additional modes of investigation. Reclassification often takes years due to the novelty of variants identified. This case highlights the importance of laboratory scrutiny when multiple variants are detected, the need for greater data sharing between laboratories to reduce inconsistent classifications, and the utility of ancillary testing, such as methylation studies, to aid in VUS reclassification.
Genetic Variations in , , , and and Their Associations with the Predisposition and Progression of Myeloproliferative Disorder and Chronic Myeloid Leukemia Patients.
Al-Amer OM, Alasseiri MI, Tayeb FJ … +15 more , Alanazi MA, Hamadi A, Jalal MM, Altayar MA, Almotairi RM, Niaz HA, Moawadh M, Alatawi S, AlZamzami W, Oyouni AAA, Alassiri M, Alharthi F, Althagafi HA, Alanazi MA, Mir R
Mol Syndromol · 2025 Dec · PMID 41378237 · Full text
INTRODUCTION: Prior research on the genotype and allele variations of immunometabolism genes and their correlations with the risk of myeloproliferative neoplasms (MPNs) and chronic myeloid leukemia (CML) is inconsistent....
INTRODUCTION: Prior research on the genotype and allele variations of immunometabolism genes and their correlations with the risk of myeloproliferative neoplasms (MPNs) and chronic myeloid leukemia (CML) is inconsistent. AIM: This study aimed to assess the correlations between mutations in specific immunometabolism genes with the risk and progression of MPN and CML in Saudi patients. METHODS: This case-control study included 244 Saudi patients, 122 patients with MPNs and CMLs, and 122 healthy controls. Immunometabolism genes, including (rs2927488 G>A), (rs11801299 G>A), (rs972283 G>A), and (rs2910164 C>G), were identified via tetra amplification-refractory mutation system PCR. RESULTS: In comparison to healthy persons, MPN and CML patients exhibited a higher prevalence of genotype and allele variants in immunometabolism genes, (, (), (), and () DISCUSSION AND CONCLUSION: The prevailing inheritance model suggested that mutations in all four immunometabolism genes were significantly correlated with an elevated chance of developing MPNs, with increases of 1.84-, 2-, 4.28-, and 2.75-fold for BCL3, MDM4, KLF14, and miR-146a, respectively, in comparison to healthy controls. In addition, we assessed the effect of gene polymorphisms on the course of the disease, and rapid disease progression was found to be correlated with the presence of these polymorphisms. These findings could help determine the risk of developing MPNs and patient prognosis.
Cobalamin J Disorder in a Teenage Boy with Recurrent Abdominal Pain Attacks: A Case Report and Literature Review.
Aslan D, Uctepe E, Yesilyurt A … +2 more , Esen FN, Dalgıç B
Mol Syndromol · 2025 Dec · PMID 41378236 · Full text
INTRODUCTION: Cobalamin J disease (CblJ) is an ultrarare autosomal recessive disorder of intracellular cobalamin metabolism associated with combined methylmalonic academia and homocystinuria (MAHCJ; 614857). CASE PRESENT...
INTRODUCTION: Cobalamin J disease (CblJ) is an ultrarare autosomal recessive disorder of intracellular cobalamin metabolism associated with combined methylmalonic academia and homocystinuria (MAHCJ; 614857). CASE PRESENTATION: A new patient with MAHCJ, representing the eighth documented instance, is reported here. A novel homozygous missense variant c.1591C>T (p.Arg531Trp) in exon 17 of (NM_005050.4) was identified. The patient, a 15-year-old male of Azerbaijani descent, presented with severe abdominal pain beginning at the age of 1 year. These episodic pain attacks were accompanied by hypotonia, pallor, nausea, and vomiting. Initial evaluations were inconclusive. At the age of 8 years, the patient developed megaloblastic anemia due to vitamin B12 deficiency, leading to the initiation of replacement therapy. The pain attacks ceased during treatment but recurred whenever vitamin B12 levels dropped after discontinuation. The patient exhibited no dysmorphology, skin hyperpigmentation, somatic abnormalities, seizures, or neurodevelopmental delays and remains in remission with ongoing vitamin B12 treatment. DISCUSSION: This patient is the oldest diagnosed with MAHCJ and has the longest documented clinical course. This report expands the known clinical and molecular spectrum of this rare disease. We recommend remembering cobalamin defects in the differential diagnosis of unresolved abdominal pain attacks.
A New Case of Nager Syndrome as a Rare Cause of Acrofacial Dysostosis.
Aglamis Senel O, Kilic E
Mol Syndromol · 2025 Dec · PMID 41378235 · Full text
INTRODUCTION: Nager acrofacial dysostosis (#154400) is a rare and mostly sporadic malformation syndrome characterized by craniofacial and extremity findings. In the study, a new case diagnosed in the neonatal period will...
INTRODUCTION: Nager acrofacial dysostosis (#154400) is a rare and mostly sporadic malformation syndrome characterized by craniofacial and extremity findings. In the study, a new case diagnosed in the neonatal period will be presented. CASE PRESENTATION: The neonatal intensive care unit consulted with our pediatrics genetic clinic for a 2-week-old male patient, who was being followed up in their unit, due to his dysmorphic findings and extremity defects. In the physical examination, downward palpebral fissures, zygomatic bone hypoplasia, mandibular hypoplasia, retromicrognathia, bilateral microtia, bilateral external auditory canal atresia, and bilateral thumb agenesis were observed. Direct radiographs showed left radius hypoplasia and bilateral thumb agenesis. Nager syndrome was considered in the presence of typical craniofacial findings, preaxial extremity deformities, and radiological findings. In the sequence analysis, c.737dupC p.(V247Sfs*239) heterozygous variant was detected. CONCLUSION: As a result of the segregation analysis, it was demonstrated that the variant was de novo. Nager acrofacial dysostosis should be considered in the patients with craniofacial malformations and radial ray findings.
WDR81 Mutation in Two Siblings: A Case Report and Review of Literature.
Öztürk MK, Canbek S, Yücel PP
Mol Syndromol · 2025 Oct · PMID 41245233 · Full text
INTRODUCTION: The gene is critically involved in autophagy, endosomal trafficking, and neurodevelopment. Pathogenic variants in this gene are associated with autosomal recessive disorders, such as cerebellar ataxia, int...
INTRODUCTION: The gene is critically involved in autophagy, endosomal trafficking, and neurodevelopment. Pathogenic variants in this gene are associated with autosomal recessive disorders, such as cerebellar ataxia, intellectual disability, and disequilibrium syndrome. Despite recent advances, the full phenotypic spectrum remains incompletely characterized. CASE PRESENTATION: We report two female siblings carrying a homozygous missense variant in the gene. The elder sister (age 15) presented with developmental regression, optic atrophy, motor neuropathy, and pes equinovarus. The younger sister (age 6) exhibited astigmatism, gait disturbance, and mild intellectual disability. Both were born to apparently non-consanguineous parents. Genetic testing confirmed the variant in both patients, and their clinical findings were compared with previously reported cases in the literature. CONCLUSION: These cases expand the clinical spectrum of -related disorders. Our observations highlight the gene's central role in neurodevelopment and emphasize the need for further investigation into its diverse systemic effects.
Personalized Treatment in Rare Genetic Syndromes: A Case-Report in Witteveen-Kolk Syndrome (SIN3A).
Janssen V, van Dongen LCM, Custers MCC … +3 more , Willemsen MH, Kleefstra T, Egger JIM
Mol Syndromol · 2026 Jun · PMID 41245232 · Full text
INTRODUCTION: Neurodevelopmental disorders (NDDs) include a broad spectrum of disorders. NDDs caused by rare gene mutations are referred to as Rare Genetic Neurodevelopmental Syndromes (RGNS). Witteveen-Kolk syndrome (WI...
INTRODUCTION: Neurodevelopmental disorders (NDDs) include a broad spectrum of disorders. NDDs caused by rare gene mutations are referred to as Rare Genetic Neurodevelopmental Syndromes (RGNS). Witteveen-Kolk syndrome (WITKOS) is such a RGNS, caused by heterozygous mutations in SIN3A and characterized by developmental problems, facial dysmorphisms, short stature, brain abnormalities, intellectual disability, and behavioral problems. Care for individuals with WITKOS mainly focuses on somatic characteristics. To address this issue, we present a case study of the first documented treatment of behavioral problems in WITKOS. CASE PRESENTATION: The patient is a 27-year-old single female with known developmental problems during childhood and a history of severe psychiatric problems. She received the genetically confirmed diagnosis of WITKOS at the age of 25 and based upon extensive intellectual and neuropsychological examination, a personalized psychological treatment could be performed. This treatment consisted of twelve individual sessions aimed to reduce anxiety, fatigue and thought disorder by treating factors contributing to cognitive overload. Evaluation during treatment and at 3-month follow-up showed a positive increase in functioning and acceptance as well as the acceptance of successive follow-up treatment. However, she was unable to maintain favorable changes in emotion-regulation strategies at follow-up, emphasizing the need for prolonged professional guidance and support. CONCLUSION: Neurocognitive evaluation enabled the adaptation of treatment strategies to the patients developmental and neurocognitive functioning, provided guidance in treatment choice, supported the rewriting of her personal narrative and resulted in successive care.
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