Molecular Syndromology[JOURNAL]
Sun
200 papers
Broken and Reassembled: The Molecular Mechanisms and Clinical Consequences of Structural Genomic Variation.
Ullah MF
Mol Syndromol · 2026 Apr · PMID 42389213 · Full text
BACKGROUND: Structural variants (SVs) are a major class of genomic variation that profoundly influences human genetic diversity, evolution, and disease. Historically underappreciated due to detection challenges, SVs are...
BACKGROUND: Structural variants (SVs) are a major class of genomic variation that profoundly influences human genetic diversity, evolution, and disease. Historically underappreciated due to detection challenges, SVs are now recognized as key drivers of both constitutional disorders and cancer. Understanding their origins and consequences is fundamental to modern genomics and clinical medicine. SUMMARY: SVs arise from the complex interplay between endogenous sources of DNA damage - such as reactive oxygen species, replication stress, and transcription-replication conflicts - and error-prone repair mechanisms including non-allelic homologous recombination, microhomology-mediated end joining, fork stalling and template switching, and break-induced replication. The formation and patterns of these variants are critically constrained by the three-dimensional architecture of the nucleus, particularly topologically associating domains, which determine the spatial proximity of potential translocation partners. Key insights into these processes are provided by genomic instability syndromes (e.g., Bloom syndrome, Fanconi anemia, Werner syndrome, Nijmegen breakage syndrome), where specific repair pathway defects result in characteristic SV signatures and clinical phenotypes. Similarly, cancer genomes serve as detailed molecular archives of repair failures, with distinct SV patterns now enabling prediction of underlying deficiencies such as loss. Thus, the pattern of SVs in a tumor genome can serve as a retrospective molecular archive of underlying repair failure, enabling 'signature-based' prediction of HR deficiency even when germline BRCA status is unknown. Emerging technologies, especially long-read sequencing, have revolutionized the field by achieving >95% sensitivity for SV detection and resolving previously intractable rearrangements. Furthermore, recent discoveries regarding biomolecular condensates in DNA repair (e.g., PARP1, MRNIP phase separation) reveal previously unrecognized regulatory layers governing repair pathway choice and SV formation. KEY MESSAGES: (i) SVs are generated by specific DNA lesions and error-prone repair processes, with their patterns shaped by nuclear architecture and three-dimensional genome organization. (ii) Genomic instability disorders and cancer genomes provide crucial mechanistic insights by linking specific repair pathway defects to characteristic SV signatures. (iii) Technological advances, particularly long-read sequencing, now enable comprehensive and sensitive detection of SVs, including those in complex repetitive regions. (iv) A unified framework for understanding SVs as products of DNA damage, cellular metabolism, and chromatin context has profound clinical implications for diagnostic reverse phenotyping, synthetic lethality strategies in oncology, and the development of targeted therapies.
Maternally Inherited Atypical 22q11.2 Microduplication Presenting with Unilateral Microtia and Aural Atresia: A Case Report of Evidence for an Association with Severe Ear Malformations.
Kim HH, Jang W, Kim N … +1 more , Park J
Mol Syndromol · 2026 Apr · PMID 42369771 · Full text
INTRODUCTION: 22q11.2 Microduplication syndrome is a genomic disorder characterized by extreme phenotypic variability and reduced penetrance. While minor ear anomalies are common, severe malformations like microtia and a...
INTRODUCTION: 22q11.2 Microduplication syndrome is a genomic disorder characterized by extreme phenotypic variability and reduced penetrance. While minor ear anomalies are common, severe malformations like microtia and aural atresia are rarely reported. We present a unique case of maternally inherited 22q11.2 microduplication with severe external ear defects but superior neurodevelopment. CASE PRESENTATION: A male neonate was diagnosed with a 2.7-Mb atypical proximal 22q11.1-q11.21 duplication involving 0.7-Mb LCR22A-LCR22B region via chromosomal microarray analysis. Multiplex ligation-dependent probe amplification confirmed the duplication was inherited from his phenotypically normal mother. Clinical evaluation revealed Marx grade III microtia and complete aural atresia of the right ear, along with mild pulmonary stenosis. Despite these physical findings, the patient demonstrated exceptional cognitive outcomes, achieving a full-scale IQ of 135 and advanced language skills at 36 months. CONCLUSION: This case described a rare and atypical inherited 22q11.2 microduplication and expands the phenotypic spectrum of the syndrome associated with this genomic disorder by associating it with severe primary ear malformations. The presence of dosage-sensitive genes like , , and likely drives these craniofacial anomalies and may help explain the phenotypic overlap with the Oculo-Auriculo-Vertebral Spectrum.
Novel Clinical and Genetic Findings in Laurin-Sandrow Syndrome: A Case Report.
Prasun P, Watkin KJ
Mol Syndromol · 2026 Apr · PMID 42369770 · Full text
INTRODUCTION: Laurin-Sandrow syndrome is a very rare developmental disorder characterized by polysyndactyly of the hands and feet, as well as nasal anomalies. Often, there is associated ulnar and/or fibular duplication....
INTRODUCTION: Laurin-Sandrow syndrome is a very rare developmental disorder characterized by polysyndactyly of the hands and feet, as well as nasal anomalies. Often, there is associated ulnar and/or fibular duplication. It is caused by microduplications on chromosome 7q36 that encompass the Sonic hedgehog limb enhancer region, the zone of polarizing activity regulator sequence (ZRS). CASE PRESENTATION: We describe here an individual with triplication encompassing the ZRS region. In addition to the other characteristic features of this condition, he has an unerupted single central maxillary incisor tooth. CONCLUSION: Laurin-Sandrow syndrome is caused by interrupted signaling of Sonic hedgehog pathway due to duplications encompassing its enhancer region (ZRS) on chromosome 7q36. ZRS plays a crucial role in limb development by regulating the Sonic hedgehog signaling. Nasal anomalies are well-recognized features of Laurin-Sandrow syndrome. Single median maxillary central incisor has not been described in Laurin-Sandrow syndrome, but it is associated with Sonic hedgehog signaling interruption. The presence of nasal anomalies and dental abnormality in Laurin-Sandrow syndrome may suggest a potential role of ZRS in craniofacial development beyond its known role in limb development.
Acute Liver Failure following Valproate Exposure in a Teenager with Homozygous POLG c.2243G>C (p.Trp748Ser) Mutation: Late-Onset Presentation and Successful Liver Transplantation - A Case Report.
Bingol I, Umur O, Sık SG … +3 more , Yilmaz TU, Emiroglu R, Citak A
Mol Syndromol · 2026 Apr · PMID 42369769 · Full text
INTRODUCTION: Valproic acid (VPA)-induced acute liver failure (ALF) is a severe and potentially fatal complication, particularly in pediatric patients with mitochondrial dysfunction. Mutations in the polymerase gamma ()...
INTRODUCTION: Valproic acid (VPA)-induced acute liver failure (ALF) is a severe and potentially fatal complication, particularly in pediatric patients with mitochondrial dysfunction. Mutations in the polymerase gamma () gene, especially those associated with Alpers-Huttenlocher syndrome, significantly increase susceptibility to VPA hepatotoxicity. CASE PRESENTATION: We report a previously healthy 17-year-old girl who developed ALF after 1 month of VPA therapy prescribed for refractory focal seizures. Despite prompt discontinuation of VPA, she developed progressive jaundice, coagulopathy, hyperammonemia, and hepatic encephalopathy. Liver biopsy revealed microvesicular steatosis and centrilobular necrosis, consistent with drug-induced liver injury. Her condition deteriorated with hypertension, refractory seizures, and radiological features of posterior reversible encephalopathy syndrome (PRES). Whole-exome sequencing identified a NM_002693.3():c.2243G>C (p.Trp748Ser; p.W748S). Due to worsening hepatic function and neurological status, she underwent emergency orthotopic liver transplantation. Post-transplantation, liver function normalized, and seizures became intermittently controllable with levetiracetam and topiramate. CONCLUSION: This case is notable for its late adolescent onset, homozygous c.2243G>C (p.Trp748Ser) genotype, association with PRES, and successful emergency liver transplantation, thereby expanding the clinical spectrum of -related VPA-ALF. These findings underscore the importance of testing prior to VPA exposure in patients with suspected mitochondrial disease, even beyond early childhood.
A Novel Intracellular Domain Missense Variant in Associated with Early-Onset Neurodevelopmental Encephalopathy.
Yigit ZM, Kayilioglu H, Yeniceri IO
Mol Syndromol · 2026 Apr · PMID 42358513 · Full text
INTRODUCTION: Biallelic pathogenic variants in the gene, which encodes the metabotropic glutamate receptor 7 (mGlu7), have been associated with early-onset neurodevelopmental disorders characterized by epilepsy, develop...
INTRODUCTION: Biallelic pathogenic variants in the gene, which encodes the metabotropic glutamate receptor 7 (mGlu7), have been associated with early-onset neurodevelopmental disorders characterized by epilepsy, developmental delay, and white matter abnormalities. However, reported cases predominantly involve variants affecting the extracellular or transmembrane domains, and the full phenotypic spectrum remains unclear. CASE PRESENTATION: We present the case of a male patient exhibiting early-onset focal epilepsy, global developmental delay, and neuroimaging evidence of corpus callosum thinning alongside normal myelination. Clinical exome sequencing identified a novel homozygous missense variant in the intracellular C-terminal domain of (c.2528C>T; p.(Pro843Leu)). This variant is present at extremely low frequency in population databases and has not been reported in the homozygous state. It also affects a highly conserved residue. In silico prediction tools support the assessment of its pathogenicity. While the patient's clinical features partially overlap with those reported in other -associated cases, they are notable for the absence of primary microcephaly and the presence of isolated motor delay, along with preserved myelination. CONCLUSION: This report adds further clinical and genetic evidence to the growing literature on -associated neurodevelopmental disorders and highlights the potential relevance of intracellular domain variants, which are underrepresented in the current literature. should be included in diagnostic gene panels for infantile-onset epilepsy and developmental delay, particularly in populations with high consanguinity rates. Further functional studies are needed to clarify the impact of intracellular variants on receptor signaling and clinical outcome.
Molecular Genetic Confirmation of Jaffe-Campanacci Syndrome: A Case Report of the Third Identified Pathogenic Variant.
Kolkiran A, Bir FD, Ergün BA … +3 more , Daylak A, Citirik M, Kulalı MA
Mol Syndromol · 2026 Apr · PMID 42292757 · Full text
BACKGROUND: Jaffe-Campanacci syndrome (JCS) is a rare phenotypic variant of neurofibromatosis type 1 (NF1), characterized by café-au-lait macules (CALMs), multiple non-ossifying fibromas (NOFs), and occasionally central...
BACKGROUND: Jaffe-Campanacci syndrome (JCS) is a rare phenotypic variant of neurofibromatosis type 1 (NF1), characterized by café-au-lait macules (CALMs), multiple non-ossifying fibromas (NOFs), and occasionally central giant cell granulomas (CGCG) of the jaw. Although fewer than 30 cases have been reported to date, molecular genetic confirmation remains limited. This report presents the third known case of a confirmed pathogenic variant. CASE PRESENTATION: A 13-year-old boy with a history of multiple CALMs, axillary and inguinal freckling, Lisch nodules, and multiple NOFs in the lower extremities was diagnosed with JCS. Genetic testing revealed a pathogenic splice-site variant in , confirming the molecular diagnosis. In addition, Sanger sequencing of DNA extracted from the affected cystic lesion tissue obtained during surgery identified the same variant, further supporting the diagnosis. Radiological findings, including lytic bone lesions in the lower extremities and brain MRI changes consistent with NF1, further supported this diagnosis. The patient also presented with a mild intellectual disability and attention-deficit/hyperactivity disorder. DISCUSSION: This case highlights the clinical challenges and diagnostic complexity of JCS, which is a rare subtype of NF1. The patient's molecular confirmation adds to the growing body of evidence, supporting genetic testing of rare variants. The absence of CGCGs in this case underscores the broad phenotypic spectrum of JCS. A comprehensive evaluation, including molecular testing, is critical for accurate diagnosis and management. CONCLUSION: This case reinforces the importance of considering rare NF1 subtypes, such as JCS, in patients presenting with multiple NOFs and typical skin findings. Early genetic confirmation is invaluable for guiding diagnosis and management, emphasizing the need for a multidisciplinary approach in rare genetic syndromes.
CHOPS Syndrome: A Rare Malformation Syndrome with de novo AFF4 Gene Variant.
Gokdemir I, Cetin SK, Kilic E … +4 more , Buyukyilmaz G, Deligozoglu D, Gurbuz F, Boyraz M
Mol Syndromol · 2026 Mar · PMID 42273204 · Full text
INTRODUCTION: CHOPS syndrome is a rare, multisystem disorder caused by heterozygous pathogenic variants in the gene. The acronym CHOPS is characterized by Cognitive impairment and coarse facial features (C), Heart defec...
INTRODUCTION: CHOPS syndrome is a rare, multisystem disorder caused by heterozygous pathogenic variants in the gene. The acronym CHOPS is characterized by Cognitive impairment and coarse facial features (C), Heart defects (H), Obesity (O), Pulmonary involvement (P), and Short stature/skeletal dysplasia (S). The syndrome is caused by variants in , which encodes a protein critical for RNA polymerase II elongation and transcriptional regulation. CASE PRESENTATION: A 6-year-old male patient with CHOPS syndrome was diagnosed with a heterozygous de novo c.764C>T (p.Ala255Val) variant in . The patient exhibited significant growth failure despite an adequate growth hormone response. Also, the patient presented with impairment, dysmorphic features, and neuroimaging findings indicative of cortical atrophy and corpus callosum hypoplasia. Additional features included congenital cataracts, laryngomalacia, and mild mitral insufficiency. CONCLUSION: This case report of CHOPS syndrome, caused by a de novo variant, highlights the multifactorial nature of growth and neurodevelopmental disturbances. Early genetic diagnosis and a multidisciplinary approach are essential for optimal patient care.
SHH Variant in a Father and a Son with Tracheobronchial Malformation.
Knottnerus SJG, Prevaes SMPJ, Geerlings MJ … +5 more , Kamsteeg EJ, Nijman J, de Jong PA, de Bie CI, Vorselaars ADM
Mol Syndromol · 2026 Mar · PMID 42266597 · Full text
INTRODUCTION: Congenital tracheobronchial stenosis (CTBS) is a rare disease of in most cases unknown etiology. In a previous cohort of patients with CTBS, a mosaic variant in the gene was identified. CASE PRESENTATION:...
INTRODUCTION: Congenital tracheobronchial stenosis (CTBS) is a rare disease of in most cases unknown etiology. In a previous cohort of patients with CTBS, a mosaic variant in the gene was identified. CASE PRESENTATION: We hereby report a son (case 1) and his father (case 2) with tracheobronchial malformation. In the severely affected proband, a rare variant (c.376G>A p.[Glu126Lys]) was found, which appeared to be inherited from his father who had a similar clinical phenotype. This variant was found to be de novo in the father. CONCLUSION: We identified a variant in as a possible cause of familial tracheobronchial malformation. This case underscores a possible association between the gene and trachea development. Notably, this variant can present with severe symptoms in infancy, but signs and symptoms may be more attenuated in adulthood.
Role of Hyperlipidemia-Related , , and Variants in Restenosis after Stent Implantation in Male Patients: A Case-Control Study.
Ozkara G, Aslan EI, Ser OS … +6 more , Kilicarslan O, Kucukhuseyin O, Bostan C, Yildiz A, Ozturk O, Yilmaz-Aydogan H
Mol Syndromol · 2026 Mar · PMID 42253317 · Full text
INTRODUCTION: This study aimed to evaluate the contribution of hyperlipidemia-related genetic variants, including protein convertase subtilisin/kexin type 9 (; rs374603772, rs67608943, rs2182833, rs11206510), apolipoprot...
INTRODUCTION: This study aimed to evaluate the contribution of hyperlipidemia-related genetic variants, including protein convertase subtilisin/kexin type 9 (; rs374603772, rs67608943, rs2182833, rs11206510), apolipoprotein E () epsilon alleles, and low-density lipoprotein receptor-related protein 8 (, also known as ; rs5174) to restenosis susceptibility in male patients with coronary artery disease (CAD) following stent implantation. METHODS: A case-control design was applied, including male patients who developed restenosis (R; = 85) and those without restenosis after stenting (OS; = 66). Genetic variants were analyzed using fluorescent end-point PCR, and genotype-phenotype associations were assessed in relation to metabolic and clinical parameters. RESULTS: Compared with the OS group, patients in the R group exhibited higher LDL cholesterol levels, increased prevalence of hyperlipidemia, and lower HDL cholesterol levels (all < 0.05). After correction for multiple comparisons, genotype analysis showed that the rs5174 AA genotype was more prevalent in the R group ( = 0.009). No significant differences were observed for epsilon, rs2182833, or rs11206510 genotypes. Notably, within the R group, the rs2182833 AA genotype was more frequently observed among nondiabetic and normolipidemic patients, indicating a possible association with a more favorable metabolic profile. Multivariate analysis identified hyperlipidemia and the rs5174 AA genotype as independent risk factors for restenosis. CONCLUSION: These findings suggest rs5174 polymorphism may act as a potential modifier for restenosis risk in male patients with CAD. Furthermore, the observed association between rs2182833 and metabolic traits appears suggestive and context-dependent. Collectively, the results underscore the potential contribution of these lipid-related genetic variations to restenosis susceptibility and highlight the need for validation in larger cohorts.
A Rare Cause of Thyroid Hormone Abnormalities in an Adolescent: A Case Report of SBP2 (SECISBP2) Deficiency.
Özdemir Akgün S, Bolaç Özyılmaz GL, Çetinçelik Ü … +2 more , Dağdeviren Çakır A, Uçar A
Mol Syndromol · 2026 Mar · PMID 42238688 · Full text
INTRODUCTION: Selenocysteine insertion sequence (SECIS)-binding protein 2 (SBP2) (SECISBP2) is essential for selenoprotein synthesis. Selenoproteins play critical roles in cellular redox homeostasis, antioxidant defense,...
INTRODUCTION: Selenocysteine insertion sequence (SECIS)-binding protein 2 (SBP2) (SECISBP2) is essential for selenoprotein synthesis. Selenoproteins play critical roles in cellular redox homeostasis, antioxidant defense, and thyroid hormone metabolism. Deiodinases (DIOs) are selenoenzymes that catalyze the deiodination of iodothyronine and are important for thyroid hormone activation and inactivation. Mutations in SBP2, which facilitates the incorporation of selenium into selenoproteins, lead to defective production of DIOs. CASE PRESENTATION: A 13-year-and-6-month-old female patient presented with constipation and abnormal thyroid function tests. Laboratory tests revealed elevated free T4 (25.5 ng/L), normal TSH (1.2 mIU/L), low free T3 (2.3 ng/L), and decreased serum selenium level (14.37 μg/L). The patient exhibited speech and language delay, along with learning difficulties. These findings suggested SBP2 deficiency. Genetic analysis revealed a previously reported homozygous pathogenic variant, c.358C>T (p.Arg120Ter) in the gene. CONCLUSION: This case highlights the importance of considering SBP2 deficiency in patients presenting with discordant thyroid function tests - namely, elevated free T4, low free T3, and normal TSH - especially when accompanied by neurological or developmental features such as speech delay and learning difficulties.
Two Siblings with Mutation: Mitochondrial Complex IV Deficiency: Case Report.
Akyüzlüer Güneş MS, Duman D, Şen EK … +6 more , Yıldırım M, Özsu E, Erdeve Ö, Kaynak Şahap S, Eminoğlu FT, Köse E
Mol Syndromol · 2026 Jun · PMID 42232680 · Full text
INTRODUCTION: Mitochondrial diseases caused by mutations in the gene are rare and lead to multisystemic dysfunction. We report two siblings from consanguineous Iraqi parents, both harboring a rare homozygous deletion in...
INTRODUCTION: Mitochondrial diseases caused by mutations in the gene are rare and lead to multisystemic dysfunction. We report two siblings from consanguineous Iraqi parents, both harboring a rare homozygous deletion in (c.2726_2728del; p.Lys909del), previously reported in one other patient. These cases contribute to the expanding phenotypic and geographic spectrum of -related mitochondrial disease. CASE PRESENTATION: The younger sibling, a 9-year-old girl, presented with severe growth retardation, global developmental delay, hypotonia, spastic ataxic gait, and lactic acidosis. Magnetic resonance imaging showed symmetrical hyperintensities in the mesencephalon and thalami, cerebellar atrophy, and an inverted lactate peak on spectroscopy. Hypertrophic cardiomyopathy was also detected. The older sibling, aged 13, exhibited milder manifestations, including axial hypotonia, tremor, ataxia, and persistent hyperlactatemia. Both siblings had elevated lactate levels but otherwise normal metabolic panels. Whole exome sequencing revealed a homozygous mutation in the gene (c.2726_2728del; p.Lys909del) in both patients. CONCLUSIONS: These cases highlight the clinical variability of -related disorders. Our report underscores the importance of considering mutations in the differential diagnosis of early-onset neurodevelopmental delay and multisystemic dysfunction with lactic acidosis, especially in populations with high rates of consanguinity. Early genetic diagnosis via whole exome sequencing is essential for accurate diagnosis, genetic counseling, and family planning.
Down Syndrome: From Pregnancy through Childhood in Türkiye.
Yilmaz Gulec E, Cetin S, Gunes M … +1 more , Gezdirici A
Mol Syndromol · 2026 Jun · PMID 42232679 · Full text
INTRODUCTION: Down syndrome is the most common genetic cause of multiple congenital malformations and intellectual disability. The prevalence of the disorder and accompanying malformations, prenatal and postnatal feature...
INTRODUCTION: Down syndrome is the most common genetic cause of multiple congenital malformations and intellectual disability. The prevalence of the disorder and accompanying malformations, prenatal and postnatal features, and clinical approach to the syndrome vary across different regions worldwide. This study aims to share our clinic's experience with Down syndrome from pregnancy through childhood from a medical geneticist's perspective and to summarize the prenatal and postnatal characteristics of our patients. METHODS: A 10-year review of medical records was conducted for patients with Down syndrome who were followed between 2010 and 2021. Patient data including sex, karyotype, follow-up period, age at first and last visit, congenital malformations, organic disorders, prenatal screening data, neonatal history, neuromotor developmental milestones, and growth parameters were evaluated. RESULTS: Overall, 324 children with Down syndrome were evaluated. Overall, 95% (308) had regular trisomy 21. The mean age at admission was 6.09 ± 1.99 months, and patients were followed for an average of 32.7 ± 3.97 months. Overall, 51% of neonates and 53.5% overall were hospitalized. While common disorders such as congenital heart defects (57.5%), neonatal hyperbilirubinemia (19.7%), and hypothyroidism (39%) were observed, rare conditions such as polydactyly, Ebstein anomaly, epilepsy, epileptic encephalopathy, nephrolithiasis, and cholelithiasis were also reported. CONCLUSION: The clinical features of Down syndrome observed in Türkiye have been summarized through our cohort. Medical teams need comprehensive knowledge about Down syndrome management. Childhood is recognized as a critical period in Down syndrome care, particularly regarding early diagnosis and treatment of congenital malformations and management of developmental delays.
Genotypic and Phenotypic Characteristics of Turkish Patients with Sjögren-Larsson Syndrome.
İcil S, Kılıç M, Sayar E … +1 more , Sezer A
Mol Syndromol · 2026 Jun · PMID 42232678 · Full text
INTRODUCTION: Sjögren-Larsson syndrome (SLS) (OMIM #270200) is an autosomal recessively inherited lipid disorder caused by pathogenic variants in gene encoding the fatty aldehyde dehydrogenase (FALDH) enzyme, that catal...
INTRODUCTION: Sjögren-Larsson syndrome (SLS) (OMIM #270200) is an autosomal recessively inherited lipid disorder caused by pathogenic variants in gene encoding the fatty aldehyde dehydrogenase (FALDH) enzyme, that catalyzes the oxidation of fatty aldehyde to fatty acid. It is a rare neurocutaneous disorder characterized by the triad of congenital ichthyosis, spasticity, and intellectual disability. The aim of study was to investigate phenotypic and molecular characteristics of Turkish patients with SLS. METHODS: Literature search was performed by entering the keywords , FALDH, SLS in TR index journal list in Turkish and PubMed in English. Turkish patients with SLS reported up to date were retrospectively analyzed. RESULTS: A total of 58 patients from 36 unrelated Turkish families were included in this study. Consanguinity was present in 73% of families. All but three patients younger than 18 months exhibited the triad of ichthyosis, developmental delay, and spastic di-/tetraplegia. Ophthalmological abnormalities were observed in 45% of patients, prematurity in 30%, epilepsy in 28%, and scoliosis in 17%. Additionally, only 2% of patients had peripheral neuropathy. Abnormal findings on brain imaging studies were detected in 84% of patients, all of whom demonstrated white matter involvement, while cerebral atrophy was present in 10%. All families had homozygous mutations, with missense in 45%, nonsense/frameshift/deletion in 35%, and splicing in 20%. Among the 15 distinct variants identified, only three, c.683G>A p.(Arg228His), c.24_25delinsTT p.(Arg9*), and c.1108-1G>C, were found to be recurrent. A review of the literature suggests that the c.24_25delinsTT p.(Arg9*) variant may be specific to the Turkish population, whereas the c.683G>A p.(Arg228His) variant appears to have a broader regional distribution across the Middle East. CONCLUSION: Although mild and severe phenotypes have been reported, the classical triad plays an important role in the preliminary diagnosis. Phenotypic findings were similar, but genotypic diversity was remarkable, and no clear genotype-phenotype correlation was observed. To make population-specific inferences, it is necessary to generate data from a larger patient cohort with haplotype analysis.
An Atypical Neurosensory-Predominant Presentation Associated with a Homozygous Variant: A Diagnostic Challenge Involving Retinal and Hearing Phenotypes.
Basan H, Kurt EE, Kasapkara ÇS
Mol Syndromol · 2026 Mar · PMID 42232357 · Full text
INTRODUCTION: Mitochondrial complex I deficiency represents a major cause of pediatric mitochondrial disease and is associated with a broad phenotypic spectrum, classically including Leigh syndrome and severe neurodegene...
INTRODUCTION: Mitochondrial complex I deficiency represents a major cause of pediatric mitochondrial disease and is associated with a broad phenotypic spectrum, classically including Leigh syndrome and severe neurodegenerative presentations. Variants in , encoding a core structural subunit of complex I, are rare and most often linked to severe multisystem involvement. However, emerging reports suggest that variants may be associated with more heterogeneous and atypical clinical manifestations. Here, we describe a child with a neurosensory-predominant phenotype presenting a diagnostic challenge involving retinal and auditory findings in the context of a homozygous variant. CASE PRESENTATION: A girl born to consanguineous parents presented with global developmental delay, bilateral digital contractures, impaired visual responses, and progressive hearing difficulties. Ophthalmologic evaluation revealed Stargardt-like maculopathy, while audiologic assessment confirmed bilateral sensorineural hearing loss. Neurological examination showed mild motor delay without neuroregression. Brain magnetic resonance imaging and spectroscopy were unremarkable, and no cardiomyopathy or metabolic crises were observed. Whole-exome sequencing identified a homozygous NDUFS3 c.721G>A (p.Ala241Thr; rs776795187) variant, classified as a variant of uncertain significance and predicted to be deleterious by multiple in silico tools (SIFT, PolyPhen-2, MutationTaster, and CADD). Heterozygous variants were also detected in ABCA4 and HMCN1. Parental segregation analysis was not available at the time of evaluation. Supportive mitochondrial therapy was initiated, and the patient remained clinically stable during long-term follow-up, with nonprogressive neurosensory findings. CONCLUSION: This case highlights the diagnostic complexity of interpreting atypical neurosensory-predominant phenotypes in mitochondrial disease. While the homozygous NDUFS3 variant may contribute to systemic mitochondrial vulnerability, the coexistence of heterozygous retinal gene variants suggests a possible modifying or oligogenic effect. Rather than defining a distinct monogenic entity, this report underscores the importance of cautious genotype-phenotype correlation and comprehensive genetic evaluation in children presenting with combined retinal and auditory involvement.
Replication-Based Mechanism Underlies a Complex dup(18p)/del(18q) Rearrangement Not Derived From Parental Inversion.
Burssed B, Zamariolli M, Favilla BP … +4 more , Brunoni D, Kulikowski LD, Bellucco FT, Melaragno MI
Mol Syndromol · 2026 Mar · PMID 42221700 · Full text
INTRODUCTION: Most intrachromosomal rearrangements characterized by terminal monosomy and trisomy concomitantly seen in different arms of the same chromosome usually arise due to pericentric inversions in parents. Forty-...
INTRODUCTION: Most intrachromosomal rearrangements characterized by terminal monosomy and trisomy concomitantly seen in different arms of the same chromosome usually arise due to pericentric inversions in parents. Forty-seven patients have been described with such alteration in chromosome 18. METHODS: We investigated a patient with dup(18p)/del(18q) whose rearrangement was characterized by karyotype, catalog and custom chromosomal microarrays, fluorescence in situ hybridization (FISH), whole genome sequencing, and Sanger sequencing. RESULTS: The patient presents a 9.7 Mb terminal duplication in 18p and a 25.8 Mb terminal deletion in 18q. The duplicated segment is inserted into the long arm of chromosome 18 in an inverted position. At the junction point, we found a 19-nucleotide segment insertion derived from a downstream 18q sequence and the presence of microhomology with both the breakpoint from the long-arm region and the one from the inverted duplicated segment from the short arm. CONCLUSION: We described, to the best of our knowledge, the fifth confirmed case of concomitant terminal trisomy and monosomy in different arms of chromosome 18 which is not due to a pericentric parental inversion, and the first with breakpoints determined at the nucleotide level. The combination of various techniques enabled us to infer the rearrangement's likely mechanism of formation. The structural features observed are consistent with replication-based mechanisms, including Fork Stalling and Template Switching and Microhomology-Mediated Break-Induced Replication. The detailed rearrangement characterization also allowed for a more detailed karyotype-phenotype correlation, which indicates that the 18q deletion is likely the cause of most of the patient's phenotypical alterations.
PHRINL Syndrome: A Case of Infantile Cataract and Cardiomyopathy.
Gülbahçe A, Deniz A, Tekin İM … +1 more , Kara B
Mol Syndromol · 2026 Apr · PMID 42199495 · Full text
INTRODUCTION: Pontocerebellar Hypoplasia, Hypotonia, and Respiratory Insufficiency Syndrome, Neonatal Lethal (PHRINL Syndrome) is a rare genetic disorder caused by impaired oxidative phosphorylation due to reduced activi...
INTRODUCTION: Pontocerebellar Hypoplasia, Hypotonia, and Respiratory Insufficiency Syndrome, Neonatal Lethal (PHRINL Syndrome) is a rare genetic disorder caused by impaired oxidative phosphorylation due to reduced activity of mitochondrial complexes I, IV, and V. The condition results from homozygous or compound heterozygous pathogenic variants in the gene, and is inherited in an autosomal recessive manner. Affected individuals typically present in early infancy with hypotonia, encephalopathy, corneal clouding, cardiomyopathy, and respiratory failure, and often die during infancy. CASE PRESENTATION: A 40-day-old female infant was referred for evaluation of a possible inherited metabolic disorder following the death of her brother at 9 months of age. No abnormalities were detected in the metabolic workup. Hypotonia was identified on physical examination at 3 months of age, brain magnetic resonance imaging (MRI) revealed pontocerebellar hypoplasia. Whole-exome sequencing (WES) identified two genetic alterations in the gene, leading to the diagnosis of PHRINL Syndrome. (NM_001170535.3: c.229C>G; p.Leu77Val) c.229C>G heterozygous missense variant was detected, along with a 0.61 kb heterozygous deletion encompassing exons 3-4 of the gene. The patient diagnosed with hypotonia at 3 months of age, developed cataracts at 5 months, and died in the eighth month due to refractory seizures. CONCLUSION: In hypotonic infants presenting with cataracts and cardiomyopathy, elevated plasma lactate levels and increased urinary excretion of 3-methylglutaconate and 3-methylglutarate may suggest PHRINL syndrome; however, the diagnosis should not be excluded solely on the basis of normal metabolic test results when characteristic clinical features are present.
Severe Thrombocytopenia and Facial Asymmetry in a Mexican Patient with Noonan Syndrome-Like Disorder with Loose Anagen Hair: Clinical Observations and Diagnostic Considerations.
León-Madero LF, Martínez-Balda AS, Venegas-Vega CA
Mol Syndromol · 2026 Mar · PMID 42181216 · Full text
INTRODUCTION: Noonan syndrome-like disorder with loose anagen hair 1 is a rasopathy caused by pathogenic variants in the gene, characterized mainly by short stature, facial dysmorphisms and ectodermal alterations. CASE...
INTRODUCTION: Noonan syndrome-like disorder with loose anagen hair 1 is a rasopathy caused by pathogenic variants in the gene, characterized mainly by short stature, facial dysmorphisms and ectodermal alterations. CASE PRESENTATION: This case describes an 18-year-old female with the pathogenic variant c.4A>G in , severe thrombocytopenia and facial asymmetry, features not currently considered part of the phenotype. While thrombocytopenia may be associated with the variant, a direct causal relationship cannot be definitively established, and the possibility of coexisting autoimmune disorders, such as systemic lupus erythematosus, could not be excluded. CONCLUSION: This case underscores the importance of early molecular diagnosis and comprehensive hematological monitoring in patients with rasopathies, highlighting the potential for life-threatening complications. Systematic reviews involving larger cohorts are needed to better define the clinical spectrum of NSLH1 and refine management strategies for potential complications.
Genotypic and Phenotypic Characteristics of Turkish Patients with Hereditary Fructose Intolerance.
Kılıç M, Sayar E, İcil S … +1 more , Sezer A
Mol Syndromol · 2026 Mar · PMID 42164825 · Full text
INTRODUCTION: Hereditary fructose intolerance (HFI) is an autosomal recessive inherited metabolic disorder characterized by a deficiency of the fructose-1-phosphate aldolase (aldolase B) enzyme, caused by biallelic patho...
INTRODUCTION: Hereditary fructose intolerance (HFI) is an autosomal recessive inherited metabolic disorder characterized by a deficiency of the fructose-1-phosphate aldolase (aldolase B) enzyme, caused by biallelic pathogenic variants in the gene on chromosome 9q31.1. METHODS: We retrospectively analyzed the demographic, clinical, biochemical, and molecular genetic characteristics of 9 patients from eight unrelated Turkish families diagnosed with HFI over the past 10 years at a single center. RESULTS: Patients with HFI showed an aversion to sugar-containing foods and generally had a favorable prognosis. The most common presenting complaints or reasons for referral to our clinic in this cohort were vomiting, hepatosteatosis, and elevated transaminases. Fructose aversion was present in all patients, representing a protective adaptive behavior rather than a complaint, and was therefore not reported as a symptom. Hypoglycemic syncope was observed in only 1 patient, while no significant hypoglycemia or metabolic acidosis was detected in the others. Urinary reducing substances and urine sugar chromatography were negative, likely due to the avoidance of fructose-containing foods. The p.Ala150Pro and p.Ala175Asp were identified as the most frequent variants. Homozygous variants (87.5%) were more common than compound heterozygous variants (12.5%). CONCLUSION: Genetic analysis of the gene should be performed in patients with clinically suspected HFI to confirm the diagnosis. The p.Ala150Pro and p.Ala175Asp variants were the most frequent, consistent with previous reports in Turkish patients and individuals of European ancestry.
IFT43-Related Cranioectodermal Dysplasia Type 3: Clinical and Molecular Insights from the First Reported Turkish Patient.
Kocagil S, Gölcür H, Aynacı S … +1 more , Çilingir O
Mol Syndromol · 2026 Mar · PMID 42137187 · Full text
INTRODUCTION: Cranioectodermal dysplasias (CEDs) are clinically and genetically heterogenous group of rare autosomal recessive ciliopathies characterized by craniofacial dysmorphism, skeletal and ectodermal anomalies, gr...
INTRODUCTION: Cranioectodermal dysplasias (CEDs) are clinically and genetically heterogenous group of rare autosomal recessive ciliopathies characterized by craniofacial dysmorphism, skeletal and ectodermal anomalies, growth retardation, and renal involvement. To date, approximately 100 affected individuals have been reported in the literature and IFT43-associated CED type 3 is one of the rarest subtypes. CASE PRESENTATION: We report the third patient diagnosed with CED type 3, presenting with typical features of the disorder, including postaxial polydactyly, dolichocephaly, frontal bossing, and ectodermal abnormalities, along with normal neurological development, and follow-up findings over a 7-year period. Whole-exome sequencing revealed compound heterozygous pathogenic variants in the gene NM_001102564.3:c.55-1G>A and NM_001102564.3:c.175C>T (p.Arg59*). CONCLUSION: We believe this patient contributes to the limited number of reported -related CED type 3 cases and expands our knowledge of this rare ciliopathy. Further research is required to more precisely characterize the clinical presentation and to better understand genotype-phenotype associations.
-Related Neurodevelopmental Disorder: Two Turkish Cases with Novel Truncating Variants and Literature Review.
Manav Yigit Z, Ozyavuz Cubuk P, Bayrak KU … +2 more , Duz MB, Yuksel A
Mol Syndromol · 2026 Mar · PMID 42125344 · Full text
INTRODUCTION: -related neurodevelopmental disorder (-NDD; neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features; MIM: 616579) is a rare autosomal-dominant condition caused by de novo trun...
INTRODUCTION: -related neurodevelopmental disorder (-NDD; neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features; MIM: 616579) is a rare autosomal-dominant condition caused by de novo truncating variants leading to haploinsufficiency. The phenotype is characterized by global developmental delay, intellectual disability, severe speech impairment, hypotonia, distinctive craniofacial features, and variable multisystem involvement. CASE PRESENTATION: We describe two unrelated girls harboring novel de novo truncating variants. Both presented with global developmental delay, profound speech impairment, hypotonia, postnatal growth impairment, and characteristic craniofacial features. Neuroimaging demonstrated normal findings in 1 patient and a thin corpus callosum in the other. Additional manifestations included high-grade vesicoureteral reflux in one individual and sensory dysregulation, reduced pain sensitivity, early-onset hyperphagia, and recurrent respiratory infections in the other. Perinatal complications were noted in one case; however, the overall phenotype was considered primarily attributable to the underlying genetic diagnosis. Exome sequencing identified heterozygous truncating variants, NM_032436.4:c.2081_2082del; p.Ser694* and NM_032436.4:c.2062dup; p.Glu688Glyfs*8, both confirmed as de novo and classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) criteria. CONCLUSION: These cases expand the mutational spectrum of and further delineate the phenotypic variability of this disorder, highlighting under-recognized systemic and behavioral features. Recognition of these additional clinical observations may facilitate earlier diagnosis and multidisciplinary management, although further studies in larger cohorts are required to clarify their clinical relevance.
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