Molecular Syndromology[JOURNAL]
Sun
200 papers
Genetic Analysis Strategy for Diagnosing Congenital Heart Disease.
Malgarezi de Moraes N, Diniz BL, Böttcher AK … +3 more , Nunes MR, Mergener R, Gazzola Zen PR
Mol Syndromol · 2026 Jun · PMID 41064054 · Full text
INTRODUCTION: Congenital heart defects (CHD) affect approximately 10-12 per 1,000 newborns globally, and they can be divided into simple cardiac defects or severe and complex ones. Its etiology derives from environmental...
INTRODUCTION: Congenital heart defects (CHD) affect approximately 10-12 per 1,000 newborns globally, and they can be divided into simple cardiac defects or severe and complex ones. Its etiology derives from environmental and genetic causes, with 20-30% of cases being genetic conditions ranging from alterations such as aneuploidies, monogenic defects, and copy number variations (CNVs). Even with the severity of this condition, many patients remain with an uncertain diagnosis. This study aimed to evaluate patients with CHD who are still undiagnosed but have already undergone genetic testing and evaluation and provide a guideline that can be followed in third-world countries to make CHD diagnostics faster and easier. METHOD: DNA was extracted from all patients included; first the samples were analyzed with the P311 multiplex ligation-dependent probe amplification (MLPA) kit specific to CHD, and the patients that remain undiagnostic were analyzed with the P245 MLPA kit for microdeletions. RESULTS: CNVs were identified in 36% of the patients, representing a high detection rate. CONCLUSION: The patient selection and prior clinical evaluation may explain our high detection rate, as much as the karyotype and fluorescent in situ hybridization normal results used for screening, combined with using two MLPA kits for detection.
Different Clinic, Different Diagnosis: Tyrosinemia Type 3.
Basan H, Ceylaner S, Küçükcongar Yavaş A
Mol Syndromol · 2026 Jun · PMID 41064053 · Full text
INTRODUCTION: Tyrosinemia type III is an extremely rare autosomal recessive metabolic disorder resulting from biallelic pathogenic mutations in the gene. To date, only a limited number of cases have been reported worldw...
INTRODUCTION: Tyrosinemia type III is an extremely rare autosomal recessive metabolic disorder resulting from biallelic pathogenic mutations in the gene. To date, only a limited number of cases have been reported worldwide, and the full spectrum of clinical manifestations remains incompletely understood. While neurodevelopmental abnormalities are the most commonly described features, ocular involvement has rarely been documented. CASE PRESENTATION: Here, we present a 9-month-old girl who exhibited strikingly atypical ocular symptoms characterized by persistent severe photophobia and allergic conjunctivitis at initial presentation. This combination of findings has been reported only sporadically in the literature. Biochemical and genetic investigations confirmed the diagnosis by identifying two novel heterozygous variants in the gene. Implementation of a phenylalanine- and tyrosine-restricted diet led to a marked reduction in plasma tyrosine concentrations and improvement in clinical symptoms. CONCLUSION: This case underscores the diagnostic importance of considering inherited metabolic disorders in infants presenting with severe photosensitivity and conjunctival irritation, even in the absence of other systemic features. Furthermore, it highlights the need for long-term follow-up to monitor potential neurological and ocular complications associated with persistently elevated tyrosine levels.
Confirmation of the Hotspot Variant in Responsible for Deafness, Ectodermal Dysplasia, Craniosynostosis, Ectrodactyly, and Skeletal Anomaly Spectrum.
Taşdelen E, Gönül M, Öztelcan Gündüz B … +3 more , Üner Ç, Büke A, Sezer A
Mol Syndromol · 2026 Jun · PMID 41064052 · Full text
INTRODUCTION: Heterozygous variants in have been implicated in a recently identified syndromic form of ectodermal dysplasia, distinguished by a unique combination of ectrodactyly, craniosynostosis, bilateral sensorineur...
INTRODUCTION: Heterozygous variants in have been implicated in a recently identified syndromic form of ectodermal dysplasia, distinguished by a unique combination of ectrodactyly, craniosynostosis, bilateral sensorineural hearing loss, and skeletal anomalies such as transverse limb defect, and brachydactyly. CASE PRESENTATION: We present an 11-year-old male with ectrodactyly, ectodermal dysplasia, bilateral sensorineural hearing loss, and cutaneous syndactyly in both hands. A de novo heterozygous variant, c.837_839del p.(Asn279del), in was identified in his whole exome sequencing. CONCLUSION: The results of this study emphasize the critical role of as a key gene in conditions involving ectrodactyly, craniosynostosis, bilateral sensorineural hearing loss, ectodermal features, transverse limb defect, and brachydactyly. We highlight the importance of prioritizing the recurrent p.(Asn279del) variant in genetic testing for affected individuals. Furthermore, we propose an acronym for this dominant disorder caused by the gene variants: DECES (Dominant/Deafness, Ectodermal Dysplasia, Craniosynostosis, Ectrodactyly, Skeletal anomalies).
A Rare Case of Bardet-Biedl Syndrome Caused by a Heterozygous Point Variant in BBS7 and a CNV Involved BBS7.
Yang X, Zhou X, Zhou C … +6 more , Li C, Wu S, Zhou Y, Du J, Guo X, Huang X
Mol Syndromol · 2026 Apr · PMID 41064051 · Full text
INTRODUCTION: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder classified as a multisystem nonmotile ciliopathy, primarily characterized by retinal cone-rod dystrophy, central obesity, postaxial polydac...
INTRODUCTION: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder classified as a multisystem nonmotile ciliopathy, primarily characterized by retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, kidney disease, and abnormalities of hypogonadism and genitourinary. CASE PRESENTATION: A fetus presenting with enlarged kidneys and enhanced echogenicity was identified during a prenatal screening at 17 weeks of gestation. Genetic analysis of the fetus was performed using chromosomal microarray analysis (CMA) and clinical exome sequencing (CES). The prenatal assessment yielded notable results in the fetus, with CMA and CES analysis detecting a compound heterozygous variant in the gene and a substantial deletion in the chromosomal region 4q26q27. Subsequent autopsy findings corroborate the presence of postaxial polydactyly, bilateral renal enlargement, and an accessory auricle in the fetus. CONCLUSIONS: Our study expands the range of phenotypes associated with BBS to include bilateral accessory auricle, as well as broadens the spectrum of variants linked to BBS. Our findings support the significant contribution of copy number variants to BBS, offering clinicians valuable insights for diagnosing the condition, particularly in prenatal settings.
A Novel Compound Heterozygous Variant in Cerebrotendinous Xanthomatosis: A Case Report from a Non-Consanguineous Family.
Cesur Baltacı HN, Sağlam Ada B, Yürür Kutlay N … +3 more , Tükün A, Teber ST, Coşkun T
Mol Syndromol · 2026 Apr · PMID 41064050 · Full text
INTRODUCTION: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive lipid storage disorder characterized by the accumulation of cholesterol and cholestanol in various tissues. It is caused by pathogenic var...
INTRODUCTION: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive lipid storage disorder characterized by the accumulation of cholesterol and cholestanol in various tissues. It is caused by pathogenic variants in the gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase. CASE PRESENTATION: Here, we present an 8-year-old boy with attention-deficit/hyperactivity disorder, born to non-consanguineous parents. He was referred to our center for gene analysis and genetic counseling, following the identification of a homozygous deletion in exon 6 of the gene in his mother. His plasma cholestanol levels were also elevated, supporting a diagnosis of CTX. The proband's father had a history of epilepsy and mild intellectual disability. Genetic analysis of the father revealed a novel heterozygous p.(Glu170Valfs*16) variant in the gene. Based on these findings, the proband was found to carry a compound heterozygous variant in , confirming the molecular diagnosis of CTX. After genetic counseling, treatment with chenodeoxycholic acid (CDCA) was initiated. Plasma cholestanol levels normalized, and some clinical symptoms showed improvement after 2 months of treatment. CONCLUSIONS: Early genetic screening of presymptomatic family members is critical, as timely initiation of CDCA therapy can prevent or significantly attenuate the clinical progression of CTX.
Long-Term Renal Transplant Success Is Possible in Hypoparathyroidism, Sensorineural Deafness, and Renal Dysplasia Syndrome: A Case Report.
Alvey L, Viswanath V, Owens JW … +1 more , Shillington A
Mol Syndromol · 2026 Apr · PMID 41064049 · Full text
INTRODUCTION: Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is caused by haploinsufficient variants. Renal disease is present in 72% of patients with HDR syndrome, with a widely variable...
INTRODUCTION: Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is caused by haploinsufficient variants. Renal disease is present in 72% of patients with HDR syndrome, with a widely variable age of onset and rate of progression. Overall prognosis is primarily dependent upon the severity of renal disease. Four patients have been previously reported to have kidney transplants due to HDR syndrome, but there are minimal data describing transplant outcomes. We describe a case of a 74-year-old male with HDR syndrome receiving a living related renal transplant lasting 27 years. CASE PRESENTATION: A 74-year-old male with genetically confirmed HDR syndrome due to a pathogenic c.608_609del (p.Gly203Glufs*100) variant in He developed hearing loss as an adolescent and was diagnosed with end stage renal disease at age 46. He had a living donor kidney transplant at age 47 that was well tolerated until age 73, and he is now listed for a repeat transplant. DISCUSSION: This individual previously had a clinical diagnosis of Alport syndrome, but the presence of congenital symptoms in other family members suggested an alternative diagnosis. In addition to highlighting discrepancies between Alport syndrome and HDR syndrome, this case establishes that long-term successful renal outcomes are possible in HDR syndrome. Current limited evidence suggests kidney transplantation should be readily offered to individuals with end-stage renal disease due to HDR syndrome.
A Treatable Cause of Seizures and Hyperphosphatasia: Patients with PGAP2 and PGAP3 Mutations.
Burgac E, Yoldas Celik M, Köseci B … +1 more , Koc Ucar H
Mol Syndromol · 2026 Apr · PMID 41064048 · Full text
INTRODUCTION: Hyperphosphatasia with mental retardation syndrome (HPMRS) is characterized by intellectual impairment, seizures, hypotonia, facial dysmorphism, and elevated serum alkaline phosphatase (ALP) level. HPMRS ha...
INTRODUCTION: Hyperphosphatasia with mental retardation syndrome (HPMRS) is characterized by intellectual impairment, seizures, hypotonia, facial dysmorphism, and elevated serum alkaline phosphatase (ALP) level. HPMRS has been linked to mutations in several genes including and . Here, we report 2 patients of HPMRS3 and HPMRS4 and highlight the genetic and phenotypic diversity of this disorder. CASE REPORTS: Patient 1, a 1-year-old male with developmental delay, generalized tonic-clonic seizures, and dysmorphic facial features, was found to have a pathogenic variant in the gene. Patient 2, a 1-year-old female with seizures, hypotonia, joint hypermobility, and facial dysmorphism, was found to have a pathogenic variant in the gene. Both patients exhibited elevated ALP levels. Brain MRI of patient 1 revealed periventricular hyperintense signal foci, while patient 2 showed cerebral atrophy and basal ganglia diffusion restriction. DISCUSSION: HPMRS3 and HPMRS4 share clinical features including elevated ALP levels, developmental delay, seizures, and facial dysmorphisms. Although joint hypermobility is not a common feature of HPMRS3, it was observed in our patients. Both patients responded well to high-dose pyridoxine, suggesting a potential therapeutic benefit for seizure management. This report expands the understanding of HPMRS by presenting novel genetic findings and providing insights into the clinical presentation of PGAP2- and PGAP3-related conditions.
A Family of Biallelic Pathogenic Variants Resulting in Rhizomelic Skeletal Dysplasia with Pelger-Huët Anomaly.
Dirimtekin E, Kapazan Ç, Yılmaz B … +2 more , Yanık AM, Geckinli BB
Mol Syndromol · 2025 Oct · PMID 41059452 · Full text
INTRODUCTION: The lamin-B receptor (LBR) gene has two primary functions: maintaining the structural integrity of the nuclear envelope and playing a role in cholesterol biosynthesis. Heterozygous variants in the LBR gene...
INTRODUCTION: The lamin-B receptor (LBR) gene has two primary functions: maintaining the structural integrity of the nuclear envelope and playing a role in cholesterol biosynthesis. Heterozygous variants in the LBR gene have been associated with Pelger-Huët anomaly (PHA, OMIM #169400), while homozygous or compound heterozygous mutations have been associated with rhizomelic skeletal dysplasia, with or without PHA (OMIM #618019) and Greenberg dysplasia (OMIM #215140). CASE PRESENTATION: We report a 4-year-old boy presenting with short stature and short limbs and his mother exhibiting milder findings. Genetic analysis revealed a heterozygous c.1640A>G (p.Asn547Ser) and c.43C>T (p.Arg15*) variants in the gene in both the boy and his mother. The father was identified as a heterozygous carrier of the c.43C>T (p.Arg15*) variant. Peripheral blood smears confirmed the PHA in the patient and his parents. CONCLUSION: The phenotypic differences observed between the mother and male child in our study highlight the genetic variability and regressive nature of LBR-related skeletal dysplasias. This report shows the complexity of -related phenotypes and expands the clinical spectrum of mutations in rhizomelic skeletal dysplasia with PHA.
A Novel Premature Termination Codon Mutation in TRAPPC2 Is Associated with X-Linked Spondyloepiphyseal Dysplasia Tarda.
Yasar D, Güleray Lafcı N, Karacan Küçükali G … +9 more , Araslı Yılmaz A, Özkaya Dönmez B, Yazar BT, Uçan B, Okur İ, Sarıkaya Özdemir B, Kurnaz E, Keskin M, Savaş Erdeve Ş
Mol Syndromol · 2025 Oct · PMID 41059451 · Full text
INTRODUCTION: Spondyloepiphyseal dysplasia tarda (SEDT) is an inherited disorder that is typically diagnosed in childhood or adolescence. It is characterized by disproportionate short stature and premature osteoarthritis...
INTRODUCTION: Spondyloepiphyseal dysplasia tarda (SEDT) is an inherited disorder that is typically diagnosed in childhood or adolescence. It is characterized by disproportionate short stature and premature osteoarthritis, and it frequently affects males. Here, we described a novel nonsense mutation, c.406A>T; p(Lys136Ter), in (NM_001011658.4) in a Turkish patient with X-linked SEDT. CASE PRESENTATION: A 15-year-old boy, born to non-consanguineous Turkish parents, exhibited a decline in height velocity over 3 years and complained of back pain despite minimal physical activity. Growth and development were normal until adolescence, with the patient's weight at 35 kg (SDS -3.85), height at 134 cm (SDS -5.44), and a predicted adult height of 137.6 cm. Dysmorphic facial features, microtia, synophrys, hypotelorism, and barrel chest were noted. Radiological examination revealed osteopenic bone structure, hypoplastic odontoid process, platyspondyly, scoliosis, short femoral necks, and coxa vara. Genetic analysis identified a hemizygous novel stop codon mutation (c.406A>T; pLys136Ter) in , also detected as heterozygous in the patient's mother. CONCLUSION: In adolescence or childhood, X-linked SEDT should be considered in cases of disproportionate short stature, short trunk, osteoarthritis, and a family history that is appropriate for X-linked inheritance. Skeletal survey should be performed to suspect SEDT, and radiological findings may support diagnosis.
Homozygous PGAP2 Mutation Causes Hyperphosphatasia with Mental Retardation Syndrome-3: Genetic and Clinical Evaluation of the Ultra-Rare Inherited Glycosylphosphatidylinositol Biosynthesis Defect.
Küçükçongar Yavaş A, Özbey SZ, Ergin B … +7 more , Ünal Y, Bilginer Gürbüz B, Karaatmaca B, Özyürek H, Oflaz O, Basan H, Kasapkara ÇS
Mol Syndromol · 2025 Oct · PMID 41059450 · Full text
INTRODUCTION: Inherited glycosylphosphatidylinositol biosynthesis defect is considered a subset of the congenital glycosylation disorder that results from mutations in the genes encoding proteins participating in glycosy...
INTRODUCTION: Inherited glycosylphosphatidylinositol biosynthesis defect is considered a subset of the congenital glycosylation disorder that results from mutations in the genes encoding proteins participating in glycosylphosphatidylinositol biosynthesis and modification. Glycosylphosphatidylinositol anchor proteins play important roles in numerous cellular processes including neurogenesis, cell adhesion, immune response, and signaling. Hyperphosphatasia with mental retardation syndrome-3 is one of the glycosylphosphatidylinositol anchor defects, characterized by moderate to severe intellectual disability, dysmorphic features, hypotonia, seizures, and persistent hyperphosphatasia. The aims of this study were to investigate the clinical implications of the gene and identify the severe phenotype. CASE PRESENTATION: A male patient with dysmorphic features, neurodevelopmental delay, seizures, hearing loss, Hirschsprung disease, central fever, and elevated alkaline phosphatase was included in the study. The magnetic resonance imaging showed cerebral atrophy and corpus callosum hypoplasia. The whole-exome sequencing analysis of the individual and Sanger sequencing were performed for segregation. Additionally, next-generation sequencing, whole transcriptome sequencing, and homology modeling and analysis were performed. Whole-exome sequencing revealed a homozygous c.651C>G (p.His217Gln) in the gene. The Sanger sequencing confirmed the parents were heterozygous. There is no splicing variant detected by whole transcriptome sequencing. The AlphaFold model was interpreted hypothetically. It observed the substitution of histidine, with glutamine, and may affect the stability of protein. DISCUSSION: Homozygous PGAP2 mutations in the patient we reported in our study resulted in a severe clinical picture including severe developmental delay and intellectual disability, severe epilepsy, dysmorphic features, central fever, biochemical, hormonal, and immunological abnormalities. This patient would be the youngest case published in the literature. We showed that the instability of mutant PGAP2 protein that causes hyperphosphatasia with mental retardation syndrome-3 leads to more severe phenotypes.
Genetics of Mitochondrial Aminoacyl-tRNA Synthetases Associated with Sensorineural Hearing Loss.
Xu B, Chai J, Bian P … +1 more , Guo Y
Mol Syndromol · 2025 Oct · PMID 41059449 · Full text
BACKGROUND: Aminoacyl-tRNA synthetases are highly conserved proteins that catalyze the tRNA aminoacylation reaction to produce aminoacyl-tRNAs involved in protein synthesis, which are required to translate cytoplasmic an...
BACKGROUND: Aminoacyl-tRNA synthetases are highly conserved proteins that catalyze the tRNA aminoacylation reaction to produce aminoacyl-tRNAs involved in protein synthesis, which are required to translate cytoplasmic and mitochondrial proteins. The mt-ARS genes encode the mitochondrial aminoacyl-tRNA synthetase (mt-ARSs), and variants in mt-ARS genes affect mitochondrial protein synthesis. This can impair the translation of mitochondrial proteins, adversely affecting oxidative phosphorylation and leading to related diseases. To date, 19 mt-ARS genes have been identified and found to be strongly associated with the development of mitochondrial disorders. Hearing loss (HL) is one of the most common chronic conditions in children and a leading cause of communication disorders. Genetic studies of sensorineural HL are critical to diagnosing and treating sensorineural HL. The relationship between mt-ARS genes and sensorineural HL is gradually surfacing as cases of HL phenotypes caused by variants in the mammalian mt-ARS genes continue to be reported. Seven mt-ARS genes have been reported to contribute to various hereditary sensorineural HL. SUMMARY: This article reviews studies on mitochondrial aminoacyl-tRNA synthetase, mt-ARS genes, and variants associated with HL phenotypes. Investigating their genetic characteristics provides deeper insights into the pathophysiology and molecular mechanisms of sensorineural hearing loss. KEY MESSAGES: Disease phenotypes resulting from variants in mt-ARS genes exhibit significant clinical heterogeneity. The varying degrees of sensorineural HL phenotypes caused by mt-ARS gene variants warrant the attention of otologists and researchers. At least seven of the currently reported mt-ARS genes are associated with sensorineural HL. However, the molecular mechanisms by which these genes contribute to HL remain incompletely understood. Further studies of the mt-ARS genes still await additional case reports, as well as related model animal studies and combined functional studies.
A Novel Variant in Two Siblings with Autosomal Recessive Intellectual Developmental Disorder-38 and Cardiomyopathy.
Şenol HB, Günay Ç, Polat Aİ … +3 more , Aydın A, Hız AS, Yiş U
Mol Syndromol · 2025 Oct · PMID 41059448 · Full text
BACKGROUND: encodes an E3 ubiquitin ligase that plays a critical role in brain development. Loss-of-function variants are associated with severe neurodevelopmental phenotypes, including intellectual disability, epilepsy...
BACKGROUND: encodes an E3 ubiquitin ligase that plays a critical role in brain development. Loss-of-function variants are associated with severe neurodevelopmental phenotypes, including intellectual disability, epilepsy, and various structural anomalies. This report aimed to expand phenotypic spectrum of -related disorders, including an unusual cardiac manifestation. CASE PRESENTATION: The proband, a male infant born to consanguineous parents, presented with myoclonia-like eyelid movements at 50-days old and subsequently developed severe neuromotor regression and choreoathetotic movements. Brain magnetic resonance imaging revealed diffuse cerebral atrophy, corpus callosum thinning, and bilateral pachygyria. He also exhibited distinct dysmorphic features and dilated cardiomyopathy, confirmed by echocardiography. His sibling presented with similar features, including severe developmental delay and dilated cardiomyopathy. Whole-exome sequencing identified a homozygous likely pathogenic c.7645C>T (p.Gln2549Ter) variant in the gene. This case report is significant as it describes dilated cardiomyopathy in MRT38, a manifestation not previously associated with HERC2 variants. The unusual cardiac phenotype suggests a potential link between HERC2 dysfunction and mitochondrial impairment, contributing to cardiomyopathy. CONCLUSION: These patients underscore the importance of recognizing novel clinical features associated with the LoF variants, which can guide disease characterization and patient management.
Hereditary Spastic Paraplegy Associated with the AP4S1 Gene: A Case Series Highlighting Diagnostic Pitfalls and Phenotypic Variability.
Günay Ç, Gazeteci Tekin H
Mol Syndromol · 2025 Oct · PMID 41059447 · Full text
INTRODUCTION: Complex hereditary spastic paraplegias (HSPs) are defined by progressive spasticity with diverse neurological manifestations, complicating the diagnostic process. Pathogenic variants in genes encoding subun...
INTRODUCTION: Complex hereditary spastic paraplegias (HSPs) are defined by progressive spasticity with diverse neurological manifestations, complicating the diagnostic process. Pathogenic variants in genes encoding subunits of the adaptor protein complex-4 (AP4), including the gene, have been implicated in a subset of HSPs. CASE PRESENTATION: We report three siblings with complex HSP harboring pathogenic gene variants, focusing on the clinical characteristics and the diagnostic challenges and pitfalls. The patients exhibited common clinical features such as progressive spasticity, distinctive craniofacial features, and neurodevelopmental delays. Neuroimaging findings included agenesis of the corpus callosum and ventricular enlargement in two siblings, whereas one sibling demonstrated normal brain imaging. Initially, these cases were misdiagnosed as cerebral palsy, leading to unwarranted surgical interventions for tethered cord syndrome. Copy number variation analysis identified homozygous deletions in the gene. CONCLUSION: In patients with progressive spasticity, seizures, distinctive craniofacial features, and neuroimaging anomalies, -related HSP should be considered in the differential diagnosis. Enhanced awareness and further studies are vital for improving diagnostic precision and management of these intricate neurogenetic disorders.
A Novel X-Linked Variant c.1772delG (p.G591fs*20) in in Two Related Patients with Central Hypothyroidism.
Köprülü Ö, Tozkır H
Mol Syndromol · 2025 Dec · PMID 41048878 · Full text
INTRODUCTION: Central hypothyroidism (CeH) is characterized by thyroid hormone deficiency due to impairment of pituitary thyroid stimulating hormone or hypothalamic TRH biosynthesis. It is extremely rare and affects appr...
INTRODUCTION: Central hypothyroidism (CeH) is characterized by thyroid hormone deficiency due to impairment of pituitary thyroid stimulating hormone or hypothalamic TRH biosynthesis. It is extremely rare and affects approximately 1:16,000-100,000 individuals. Diagnosis, especially of isolated CeH, may be challenging. CeH is often seen as a part of multiple pituitary hormone deficiencies, but it can also be seen as isolated CeH. To date, some variants that can cause CeH have been identified, although in a number of patients the cause has not been clarified. Recently, variants of the insulin receptor substrate 4 () gene have been reported to be the cause of isolated CeH. Herein, we report two related patients and their family with carriers with a novel X-linked frameshift variant in the gene. It has also been shown that thyroid function may be slightly affected in the heterozygous female carriers in our study. CASE PRESENTATION: Herein, we reported two Turkish male patients with CeH due to a hemizygous variant in . The index case was a 15-year-and-2-month-old male who presented with a low serum-free thyroxin level, which was incidentally detected. CONCLUSION: Isolated CeH should keep in mind in insistent low fT4 levels without an increase in thyroid stimulating hormone levels. Genetic testing can aid in identifying the underlying cause of CeH in such cases. This report demonstrates the significance of providing comprehensive laboratory and molecular features of the patients and carriers with the variants.
A New Family with X-Linked Intellectual Disability 90: A Case Report of a Variant and Literature Review.
Alavanda C, Çıkı K
Mol Syndromol · 2026 Apr · PMID 40881055 · Full text
INTRODUCTION: X-linked intellectual disability (XLID) is a highly heterogeneous disease. Apart from Fragile X, other diseases that cause XLID are quite rare. The gene variants cause XLID90. CASE PRESENTATION: This study...
INTRODUCTION: X-linked intellectual disability (XLID) is a highly heterogeneous disease. Apart from Fragile X, other diseases that cause XLID are quite rare. The gene variants cause XLID90. CASE PRESENTATION: This study presents 2 patients diagnosed with XLID90 after identifying a variant in the gene through whole exome sequencing analysis. Both patients had autism spectrum disorder, intellectual disability, and dysmorphism. Additionally, an arachnoid cyst, which has not been previously reported in XLID90, was also detected in the patients. XLID90 has neither specific clinical findings nor dysmorphic features. Therefore, a detailed literature review is essential for clearly elucidating the phenotype. Here, one hundred and two XLID90 cases from 18 publications reporting pathogenic variants in the gene were reviewed to investigate the detailed clinical findings among these patients. The literature review has shown that ID is more frequently observed in patients with truncating variants, while seizures are more commonly seen in patients with non-truncating variants. CONCLUSION: This study will provide homogeneous healthcare to patients and allow for appropriate genetic counseling.
A Novel Non-Canonical Splice Region Variant Associated with Gorlin Syndrome: A Case Report.
Smith MJ, Shell EJ, Burghel GJ … +4 more , Carney M, Waller SJ, Hakim A, Evans DG
Mol Syndromol · 2025 Dec · PMID 40881054 · Full text
INTRODUCTION: Gorlin syndrome (GS) is a rare autosomal dominant condition that predisposes to cutaneous basal cell carcinomas, jaw keratocysts, and skeletal anomalies. Most patients with GS have a heterozygous pathogenic...
INTRODUCTION: Gorlin syndrome (GS) is a rare autosomal dominant condition that predisposes to cutaneous basal cell carcinomas, jaw keratocysts, and skeletal anomalies. Most patients with GS have a heterozygous pathogenic variant in the gene, although a minor subset have a pathogenic variant in the gene. CASE PRESENTATION: We report a 34-year-old woman meeting clinical diagnostic criteria for GS and with an affected father who also meets diagnostic criteria. Both had a novel germline splice-region variant that was originally classified as a variant of uncertain significance. CONCLUSION: We used cDNA analysis to provide additional evidence to allow re-classification of the non-canonical splice variant and provide a formal genetic diagnosis that can also be used for family planning and to screen at-risk relatives.
Clinical and Genetic Aspects of Verheij Syndrome in Two Cases.
Kursat YD, Sezginer Guler H, Zhuri D … +2 more , Gurkan H, Yalcintepe S
Mol Syndromol · 2026 Feb · PMID 40881056 · Full text
INTRODUCTION: Verheij syndrome is associated with a deletion on chromosome 8q24.3 region or gene mutations. A variety of symptoms including feeding problems, microcephaly, joint laxity, intellectual disability, cardiac...
INTRODUCTION: Verheij syndrome is associated with a deletion on chromosome 8q24.3 region or gene mutations. A variety of symptoms including feeding problems, microcephaly, joint laxity, intellectual disability, cardiac defects, and renal abnormalities are the characteristic features of the syndrome. CASE PRESENTATION: In the current report, 2 cases are presented with Verheij syndrome in different ages. With this study, we aimed to present the clinical findings of a likely pathogenic novel variant in the first case NM_078480.3():c.297+1G>C, and in the second case a likely pathogenic heterozygous missense variant NM_078480.3():c.47G>T p.(G16V). CONCLUSION: A very rare syndrome - Verheij syndrome - is reported in 2 cases with genotype phenotype correlation in this report.
Missense Variant Met119Val in in a Patient with Baraitser-Winter Syndrome Type 1 and Mild Intellectual Disability.
Zechi-Ceide RM, Serigatto HR, Galvanin AL … +4 more , Rafacho MB, Kokitsu-Nakata NM, Guion-Almeida ML, Di Donato N
Mol Syndromol · 2025 Aug · PMID 40771191 · Full text
INTRODUCTION: The Baraitser-Winter syndrome (BRWS) is a rare condition characterized by multiple congenital anomalies and developmental delay. Most cases present moderate to severe global delay and intellectual disabilit...
INTRODUCTION: The Baraitser-Winter syndrome (BRWS) is a rare condition characterized by multiple congenital anomalies and developmental delay. Most cases present moderate to severe global delay and intellectual disability. The etiology of BRWS is heterogeneous, caused by heterozygous gain-of-function variants in or genes. CASE REPORT: Here we report on a Brazilian female patient with dysmorphic craniofacial features of the BRWS, oligodontia, partial agenesis of the corpus callosum, pineal cyst, cervical cystic hygroma, pterygium colli, axillary pterygium, duplicated left hallux, seizures, and mild developmental delay. Sanger sequencing of the gene showed the heterozygous missense variation NM_001101.5 (ACTB):c.355A>G (p.Met119Val). CONCLUSION: The clinical findings are compatible with the diagnosis of BRWS type 1. Our case includes oligodontia as a new feature of the BRWS type 1 phenotype. Functional study of the variant here described could contribute to elucidate the pathogenetic pathway that results in the severe craniofacial phenotype associated with mild developmental delay.
C.655C>T Variant of Sepiapterin Reductase Deficiency: Genetic and Bioinformatic Analysis.
Eslamiyeh H, Sefid F, Iravani F
Mol Syndromol · 2025 Aug · PMID 40771190 · Full text
BACKGROUND: Sepiapterin reductase deficiency (SRD) is a very rare psychomotor disorder related to enzyme defects in synthesizing tetrahydrobiopterin (BH4) with a spectrum of symptoms. The most common of which are develop...
BACKGROUND: Sepiapterin reductase deficiency (SRD) is a very rare psychomotor disorder related to enzyme defects in synthesizing tetrahydrobiopterin (BH4) with a spectrum of symptoms. The most common of which are developmental delay and hypotonia. To elucidate the genetic cause of SRD, the patient was analyzed by whole-exome sequencing (WES) followed by mutation analysis. METHODS: A complete clinical examination was performed by a pediatric neurologist. Brain imaging and a thorough neuro-metabolic investigation were applied along with biochemical tests including high-performance liquid chromatography (HPLC) to quantify the concentrations of cerebrospinal fluid (CSF) pterins. Genomic DNA was extracted and evaluated through WES. This was followed by bioinformatic analysis of mutated sepiapterin reductase (SPR) protein structure and identification of the functional protein amino acids. RESULTS: Biochemical analysis of biogenic amines of CSF with HPLC showed very low levels of homovanillic acid and 5-hydroxyindolacetic acid in favor of neurotransmitter metabolism disorder. WES analysis displayed a homozygous nonsynonymous variant in exon 3 of the SPR gene (C.655C>T, p.Arg219Ter). The molecular graphic of SPR protein structure with 4HWK PDB code was generated by MOE software in comparison with P.Arg219* mutated protein which is predicted by a Swiss model homology modeling server determining the ligand-binding site residues using COFACTOR software and indicated that the (R219*) mutation destroyed the ligand-binding site from the position of 219. Another important codon including 254 and 256 positions is omitted. CONCLUSION: Whole exome sequencing and bioinformatic analysis could overcome lengthy, expensive, and emotional diagnostic adventures of challenging neurodevelopmental cases leading to improved management and prevention of irreversible side effects.
Cerebrotendinous Xanthomatosis Disease Prevalence in Patients with Autism Spectrum Disorder: A Prospective Observational Study.
Karadag M, Turan MI, Celebi C … +1 more , Caglar T
Mol Syndromol · 2025 Aug · PMID 40771189 · Full text
BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive congenital metabolic disorder, which is characterized by the impairment of the enzymatic activity of sterol 27-hydroxylase. CTX, a rare neurodege...
BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive congenital metabolic disorder, which is characterized by the impairment of the enzymatic activity of sterol 27-hydroxylase. CTX, a rare neurodegenerative disease of sterol metabolism, can affect multiple systems, including the nervous system. It has been demonstrated that many congenital metabolic diseases like CTX are associated with autism spectrum disorder (ASD). The aim of this study was to identify the prevalence of CTX disease in patients with ASD. METHOD: The clinical conditions of all patients were evaluated using the Mignarri Scoring Index. A sociodemographic form and Gilliam Autism Rating Scale-2 were applied to all participants. RESULTS: In total, 101 children and adolescents with ASD were analyzed for genes. Following genetic analyses, 4 patients with mutations in the gene, two homozygous variants, and two different heterozygous mutations were identified. Most common symptom was diarrhea. Overall, 67.3% of all patients and 3 in 4 cases with gene mutation had gone through psychiatric evaluation. A family history of a psychiatric disorder was present in 19.8% of all cases and in 75% of cases with mutations. Moreover, all mutant cases had comorbid oppositional defiant disorder. A total of 81.2% of all patients and all mutant patients were diagnosed with a behavioral disorder. CONCLUSION: Psychiatric manifestations ranging from personality changes to behavioral disorders might accompany CTX. Better understanding and knowledge of the CTX disease by distinguishing specific psychiatric and systemic symptoms might help prevent missed diagnoses, progressive neurological deterioration, and permanent disability through early initiation of chenodeoxycholic acid treatment.
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