Molecular Syndromology最新文献

Background: Early infantile epileptic encephalopathy (EIEE) is a rare neurological condition characterized by frequent seizures in the early stages of life, resulting in severely impaired cognitive and motor development. Although the specific causes of EIEE remain unknown, one of the primary causes is gene pathogenicity (even in the absence of consanguinity). Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) are essential for proper brain function. They are regulated by multiple genes, and mutations in these genes induce channel malfunction, which can result in various severe conditions, including EIEE. Herein, we have reported a patient presenting hallmarks of EIEE.

Methods: The patient underwent clinical, radiographic, and genetic analysis. A thorough clinical examination and molecular study were conducted utilizing whole exome sequencing and Sanger sequencing.

Results: Whole exome sequencing of the proband revealed a novel de novo nonsynonymous/nonsense variant (c.1468A>T; (p.Lys490Ter) in exon 6 of the HCN1 gene. This variant may cause channel dysfunction via nonsynonymous/nonsense-mediated decay or aberrant protein, which may be associated with EIEE phenotypes.

Conclusions: This evidence backs the idea that HCN1 has a vital role in brain development and lose of function can cause a range of debilitating conditions. Still, the functional characterization study of the HCN1 variants will be the fundamental tool for a better understanding of EIEE in the near future.

Introduction: Metachromatic leukodystrophy (MLD) is a rare, demyelinating, autosomal recessive lysosomal storage disease caused by a deficiency in the arylsulfatase A enzyme (ASA), which is encoded by ARSA gene. A lack of ASA activity results in an accumulation of sulfatides in the myelin sheaths of both the central and peripheral nervous systems, leading to developmental and neurocognitive progressive deterioration that can be observed in all age groups.

Methods: We present a total of 9 patients with MLD with an average age of 61 months, whose clinical, laboratory and cranial magnetic resonance imaging findings were evaluated, and who underwent an ARSA gene molecular analysis.

Results: Of the 9 patients, 7 had the late infantile form of the condition, 2 had the juvenile form, and 3 were identified through family screening. The median age at diagnosis was 30 months (min 3-max 73 months), the mean ASA activity value was 2 nmol/h/mgprt and the median cranial MR imaging severity score was 10 (min 5-max 18). The grey and white matter volumes of all patients, evaluated using volBrain software, were within the normal range. At an average age of 48 months, the late-infantile MLD patients were unable to control any body part.

Conclusions: Hematopoietic stem cell transplantation (HSCT), a treatment option for both the juvenile and adult forms of MLD in asymptomatic or early symptomatic patients, was performed on two of the asymptomatic and early symptomatic patients, and post-HSCT ASA activity settled within the normal range and their developmental milestones stabilized. It is important to diagnose MLD in the asymptomatic period and newborn screening can support early diagnosis.

Introduction: Combined oxidative phosphorylation deficiency-12 (COXPD12) is a rare autosomal recessive disorder. Neurological findings and lactic acidosis can be presenting signs of COXPD12.

Case presentation: Here, we present identical dysmorphic facial features that have not been described before in the literature, in 2 patients with two different EARS2 gene variants. Case 1 was a 2.5-month-old male who presented with hypotonia and lactic acidosis. Cranial magnetic resonance imaging (MRI) showed diffusion restriction in the supratentorial deep white matter, around the ventricle, in the bilateral periaqueductal gray matter at the level of the basal ganglia, and in the dentate nuclei in the tegmentum. Case 2 was a 2-month-old boy who also presented with lactic acidosis and hypotonia. Diffusion MRI reported hypomyelination. Dysmorphic facial features including slight metopic ridge, ptosis, wide palpebral fissure length, sparse eyebrows, bulbous nose, thin upper lip, full cheeks, small chin, large ears, thin ear helix, and prominent antihelix were common findings in both patients. Molecular genetic analysis indicated c.319C>T(p. Arg107Cys) common genetic variant in our 2 patients. In case 2, the second allele was a novel genetic variant.

Conclusion: For COXPD12 disease, facial features are considered the main diagnostic clue, such as hypotonia or lactic acidosis; thus, the characteristic facial phenotype will help clinicians diagnose the disease.

Introduction: Weaver syndrome, rare syndromic cause of tall stature, presents with overgrowth, accelerated skeletal maturation, dysmorphic features, and camptodactly. Despite expanding knowledge and widespread use of genetic tests, differential diagnosis of tall statue may be challenging, complicating follow-up. Here we describe a patient with a variant in EZH2, underlining presenting features and natural course.

Case presentation: Twenty-month-old girl consulted for tall stature was born at term (birthweight: 2,600 g [-0.8 SDS], birth length: 54 cm [2.4 SDS]) as the third child of non-consanguineous parents. Without any other complaints, she was 15.2 kg (2.5 SDS) and her height was 95 cm (3.1 SDS). She was proportionately tall compared to her parents (target height: 156 cm [-1.1 SDS]). Endocrine evaluation did not reveal pathology, growth traced parallel to 97th percentile of growth curve. Karyotype analysis and fibrillin gene analysis were normal. As she had mild intellectual disability and minor dysmorphic features (broad forehead, mild hypertelorism, long philtrum, thin upper lip and a prominent chin dimple, bilateral camptodactyly), whole exome analysis including copy number variant changes that revealed a heterozygous variant on EZH2 was performed when she was 14 years old. Weaver syndrome was diagnosed.

Conclusion: Tall stature, height SDS exceeding target height SDS, tall stature at birth, normal growth rate, minor dysmorphic features, and mild intellectual disability should prompt syndromic etiology of tall stature. Further genetic analysis should be implemented. Diagnosis of rare syndromes is crucial for defining prognosis, organ involvement, and natural course, avoiding unnecessary endocrine investigations.

Introduction: Epilepsy is a group of neurologic disorders with clinical and genetic heterogeneity. Epilepsy often affects children; thus, early diagnosis and precise treatment are vital to protecting the standard of life of a child. Progress in epilepsy-related gene discovery has caused enormous novelty in specific epilepsy diagnoses. Genetic testing using next-generation sequencing is now reachable, leading to higher diagnosis ratios and understanding of the disease's underlying mechanisms. The study's primary aim was to identify the genetic etiology based on targeted next-generation sequence analysis data and to calculate the diagnostic value of the epilepsy gene panel in the 0-17 age-group diagnosed with epilepsy. The secondary aim was to demonstrate the significance of periodic reinterpretation of variant of uncertain significance (VUS) variants and genotype-phenotype correlation.

Methods: This retrospective study comprised 107 patients with epilepsy aged 8 months to 17 years, for whom a targeted gene panel covered 110 genes. VUS variants were reanalyzed, and genotype-phenotype correlation was performed.

Results: In the initial evaluation, causal variants were described in 23 patients (21.5%). After reinterpretation of VUS, we detected causal variants in 30 out of 107 patients (28%). By reinterpreting the VUS and evaluating genotype-phenotype correlations, we enhanced our diagnostic value by 30.32%. After reinterpretation of VUS variants, the ACMG classification of 36 variants, including 15 benign (31%), 15 likely benign (31%), 5 likely pathogenic (10%), and 1 pathogenic (2%), were redefined. We most frequently detected causal variants in TSC2 (n = 5), GRIN2A (n = 4), and ALDH7A1 (n = 4) genes.

Conclusion: The predictive value for epilepsy panel testing was 28% in the cohort. Our study revealed the importance of reanalysis of VUS variants and contributed to enriching the mutation spectrum in epilepsy.

Introduction: Copy number variation (CNV) is the difference in the sequence of genomic segments, which can vary from one kilobase to several megabases. Certain CNVs have been linked to various human disorders, such as intellectual disability, multiple congenital anomalies, autism spectrum disorders, neurodegenerative and neuropsychiatric conditions, and cancer. The present study aims to classify brain magnetic resonance imaging (MRI) findings, describe neurological manifestations, and discuss the findings within the context of genotype-phenotype correlations in a cohort of patients with recurrent and nonrecurrent CNVs.

Methods: A total of 21 patients with pathogenic CNV detected using microarray analysis were included in the study.

Results: Analysis of the clinical findings of the patient cohort showed that 16 (76%) had microcephaly, 14 had epilepsy (66%), 20 had facial dysmorphism (95%), and all had developmental delay (100%). Novel brain MRI findings were detected in six (6/13, 46%) patients with recurrent CNV and five (5/8, 63%) patients with nonrecurrent CNV.

Conclusion: CNV-related disorders should be considered in the differential diagnosis of patients with brain MRI findings suspicious for metabolic disorders. Brain MRI differences in patients with the same chromosomal deletion can be explained by the second-hit hypothesis. Additional single nucleotide variations and epigenetic factors in these cases may have led to the involvement of different regions of the brain. Revealing the phenotypic and genotypic characteristics of cases in rare disorders will contribute to the widespread use of precision medicine and genetic treatment approaches in the near future.

Introduction: Physicians often search for a single underlying cause that explains all of a patient's signs and symptoms. However, evidence from the literature suggests that the concurrent presence of two rare diseases, although uncommon, poses significant diagnostic challenges. Precision medicine is increasingly important in these scenarios, enabling more rapid diagnosis and tailored treatments.

Case presentation: This report discusses a patient involving a consanguineous Brazilian family, where two sisters are diagnosed with autosomal recessive KLHL24-related hypertrophic cardiomyopathy. Additionally, one sister is diagnosed with Char syndrome due to a TFAP2B deletion.

Conclusion: This case underscores the possibility that multiple rare genetic disorders can coexist, contributing to complex clinical phenotypes. Whole-exome sequencing proves to be a critical tool in identifying the genetic underpinnings of such complex cases, facilitating precise diagnosis and genetic counseling. The discovery of a homozygous KLHL24 variant further broadens the known mutation spectrum and underscores its significance in autosomal recessive hypertrophic cardiomyopathy.

Introduction: Cullin-3, encoded by the CUL3, is a core component of the ubiquitin E3 ligase complex. Through binding to specific adapters, this scaffold protein mediates the ubiquitination of a number of substrates, targeting their proteasomal degradation. Pathogenic variations of the CUL3 are thought to cause autism and neurodevelopmental disorders, but so far, few studies have been associated with the phenotype "neurodevelopmental disorder with or without autism or seizures (NEDAUS, #OMIM: 619239)." This study aimed to present the first Turkish patient with a NEDAUS phenotype exhibiting novel clinical and genotypic findings.

Case presentation: A 7-year-old patient with seizure, speech delay, decreased eye contact, and autistic behaviors was referred to our clinic. The patient was evaluated through clinical examination, laboratory tests, and imaging studies. Physical examination revealed extremity findings (brachydactyly, tapering fingers). Single whole-exome sequencing analysis was performed for clinical diagnosis. A novel missense variant, c.368T>A (p.Leu123Gln) in CUL3, was discovered in the patient. Additionally, computational studies were employed to gain structural and mechanistic insights into the putative damaging impact of the variant. Computational analyses indicated that the p.Leu123Gln substitution may affect the stability and binding behavior of cullin-3. The detected variant was confirmed by the Sanger method and screened in family members by the same method and was found to be de novo.

Conclusion: By presenting the first Turkish case of a novel missense variant with a CUL3-related NEDAUS phenotype, this study contributes to the expansion of the genotypic and phenotypic spectrum of the disease.

Introduction: The inducible degrader of low-density lipoprotein (IDOL) receptor, an E3 ubiquitin ligase, was recently identified as a regulator of the LDL receptor (LDLR) pathway. Shortly, IDOL stimulates LDLR degradation through ubiquitination. However, the association of IDOL gene variants with plasma lipid levels is controversial. No previous study in the Turkish population has reported the relationship between variants of the IDOL gene and low-density lipoprotein cholesterol (LDL-C) levels. Our study aims to investigate the effects of genetic variants in the human IDOL gene, which may be a therapeutic target in human cholesterol metabolism, on LDL-C levels.

Methods: We sequenced all coding, critical intronic, and untranslated regions of the IDOL gene in 125 controls (77 women, 48 men) and 125 patients (64 women, 61 men) with definite or probable familial hypercholesterolemia (FH) according to the criteria of the Dutch Lipid Clinic Network, in whom no pathogenic/likely pathogenic LDLR variants are present.

Results: We identified 12 different IDOL gene variants, including the p.(N342S) and p.(G51S), whose association with LDL-C levels has been investigated, and classified them into common and rare variants. A rare variant p.(G51S) was only detected in patients the patient group. We compared the minor allele frequency (MAF) distribution of common variants between patient and control groups and examined the association of their genotypic distribution with plasma LDL-C levels using genetic models (dominant, recessive, overdominant, codominant). There was no statistically significant difference in the parameters of the patient and control groups (p > 0.05).

Conclusion: Our findings suggest that the common IDOL variants we identified do not associate with the LDL-C level in the Turkish population. Rare variants that were not found to be statistically significant in our study, should be emphasized, and supported with further research.

Introduction: Noonan syndrome (NS) is a Mendelian phenotype, member of the RASopathies, a group of clinically overlapping multisystem disorders caused by germline variants in the RAS-MAPK signaling pathway genes. Among the clinical findings in NS, lymphatic abnormalities (LAs) are diagnosed in approximately 30%, mostly in individuals harboring variants in RIT1 and SOS2. This genotype-phenotype correlation is not precise, and recent evidence suggests a higher prevalence of LAs in individuals harboring variants on p.Phe285 residue in PTPN11, the main gene responsible for NS.

Case presentation: Here, we report a novel case of NS harboring the PTPN11:p.Phe285Ser variant that evolved with chylothorax and presented the rare finding of plastic bronchitis, an uncommon and underdiagnosed pulmonary disease, characterized by production of cohesive and branching casts filling the airways. We also provide a review of other individuals with NS and LA harboring variants on Phe285 residue in PTPN11 from our service and from the literature and compared its prevalence with the most commonly affected residue in PTPN11-related NS (p.Asn308), which indicated that variants in the p.Phe285 residue might predispose to LA.

Conclusion: We suggest that, when this variant is identified in an individual, clinicians should be warned of a possible higher prevalence of LA and a prompt evaluation should be performed if any clinical signs are noticed.