Molecular Syndromology最新文献

Introduction: Cholestasis in childhood is a rare clinical condition, yet a definitive diagnosis is crucial for initiating treatment of these curable diseases and preventing related morbidity and mortality. The most common cause of infant cholestasis is biliary atresia (25-40%), followed by monogenic cholestatic diseases (25%), metabolic diseases (20%), and cryptogenic cholestasis. This study focuses on assessing the clinical utility of next-generation sequencing (NGS) panels, including clinical exome sequencing and whole exome sequencing, in diagnosing cholestatic diseases when the etiology cannot be elucidated through conventional methods.

Materials and methods: We conducted a retrospective examination of pediatric patients who sought care at a single-center pediatric gastroenterology department between August 2020 and March 2022 and were diagnosed with cholestasis. A total of 36 patients underwent a thorough investigation to rule out infectious, toxic, metabolic, structural, chromosomal, and endocrine causes. Patients whose diagnoses were established through traditional investigations were excluded from the study. The remaining 14 patients underwent either whole exome sequencing or targeted NGS methods.

Results: A definitive diagnosis was achieved for 12 patients, while 2 patients remained undiagnosed despite comprehensive genetic examinations. The most commonly encountered diseases in this cohort were progressive familial intrahepatic cholestasis, linked to mutations in the ABCB11, ATP8B1, and TJP2 genes, as well as Dubin-Johnson syndrome associated with ABCC2 mutations. NGS demonstrated a diagnostic accuracy of 85.7% in patients for whom a diagnosis could not be established through extensive traditional workup.

Conclusion: NGS emerges as a valuable diagnostic tool in cases of cholestasis where traditional methods fall short in providing a definitive diagnosis. Moreover, our study unveiled three previously undocumented variants in the ABCB11 [c.1165G>C; p.(Ala389Pro) and c.783 + 1G>A] and ABCC2 [c.4246_4247del; p.(Lys1416ValfsTer46)] genes.

Introduction: Ectodermal dysplasias (EDs) represent a heterogeneous group of genetic disorders marked by impaired development of multiple tissue derivatives originating from the human ectoderm, including teeth, hair, nails, and sweat glands. Advances in next-generation sequencing technology have facilitated the identification of novel genes, such as TSPEAR, contributing to the emergence of the ectodermal dysplasia-14 of the hair/tooth type (ECTD14) phenotype, primarily characterized by hypotrichosis, hypodontia, and dysmorphic features.

Methods: Five individuals from the same family were included in the study, three of whom were heterozygous and two homozygous for a novel frameshift TSPEAR variant. All displayed ED and/or tooth loss. Exome sequencing was performed in the index case, and Sanger sequence analysis was carried out to detect the carrier status in parents and relatives.

Results: We identified a novel biallelic frameshift TSPEAR variant [NM_144991.2, c.1594_1595insA, p.(Phe532TyrfsTer26)] in two siblings who displayed oligodontia, sparse hair, and facial dysmorphism. The remaining heterozygous carriers manifested early tooth loss with non-syndromic isolated oligodontia.

Conclusion: This study has identified individuals carrying biallelic and heterozygous TSPEAR variants, where heterozygous carriers often exhibit non-syndromic tooth agenesis. Moreover, the presence of inter- and intrafamilial variability emerges as a notable feature of the disease. This understanding underscores the complexity of the disease and the importance of considering genetic variability when diagnosing and managing affected individuals.

Introduction: NOTCH3, one of the four mammalian Notch receptors, acts as a transcriptional activator in a variety of tissues. Variants in NOTCH3 lead to distinct phenotypes, depending on variant type and location. Truncating variants in the last exon generate a protein lacking the PEST domain, responsible for degradation, leading to a gain-of-function effect and causing Lateral Meningoceles syndrome (LMS), characterized by dysmorphisms and variable cardiac, skeletal, and connective tissue abnormalities; motor delay may occur, but the cognitive function is usually normal.

Case presentation: We report the first case of prenatal molecular diagnosis of LMS, which was made using prenatal exome sequencing after an ultrasound with findings of fetal cystic hygroma, mild bilateral ventriculomegaly, and facial dysmorphisms. After birth, magnetic resonance imaging confirmed the presence of lateral meningoceles. A complete clinical evaluation was performed and unexpected biliary anomalies were found.

Conclusion: The occurrence of biliary anomalies has not been previously reported in LMS but may have biological plausibility. Expression of NOTCH3 has been demonstrated in biliary development and is thought to play a role in the differentiation of hepatoblasts into biliary epithelial cells, and also in liver regeneration and repair. We hypothesize that the findings reported here might expand the phenotype of LMS.

Introduction: Pseudo-TORCH syndrome, named as such due to the mimicry of intrauterine TORCH infections in the absence of infection, is a neurological disorder presenting primarily with congenital microcephaly, intracranial calcifications, simplified gyration and polymicrogyria, and severe developmental delay, which can be attributed to variants in the OCLN gene. MCC2 deficiency, a neurometabolic disorder due to impairments in the catabolism of Leucine, with highly variable clinical presentations in addition to landmark metabolic features is put down to variants in MCCC2 gene.

Case presentation: Known as independent conditions, the intriguing presence of dual manifestations in a 3.5-year-old boy was investigated in the study. The patient was referred to our Myelin Disorders Clinic due to congenital microcephaly, developmental regression, and medication-resistant epilepsy. WES was performed on patient's samples for variant detection and subsequent confirmation. Bioinformatics analysis was performed for prioritization and validation according to the standard criteria. The resultant findings were consequently confirmed in the proband and his parents by Sanger sequencing. WES revealed the presence of two concurrent variants in OCLN and MCCC2 on the same chromosome, chromosome 5, both in homozygous state in the proband. Both variants are classified as pathogenic according to ACMG classification system having been previously reported in the literature.

Conclusion: The two variants observed in our patient, a homozygous missense change and a homozygous deletion interestingly occurring on the same chromosome, lead us to think that either these two conditions may be totally independent of each other, having co-occurred by chance, or there may be an underlying association between the two variants, rendering their co-occurrence as a haplotype more possible.

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.

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 CYP27A1 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 CYP27A1 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.

Introduction: Lipoid proteinosis (LP), a rare autosomal recessive disorder typified by generalized thickening of the skin, mucosa, and certain viscera, is associated with pathogenic ECM1 variants. Skin lesions like beaded eyelid papules, acneiform scars, wavy, yellow papules and nodules typically appear in early childhood. Some patients may exhibit neurological abnormalities like temporal lobe or hippocampi-amygdala complex calcification, epilepsy, and neuropsychiatric abnormalities.

Methods: We included 15 individuals with LP from 10 unrelated families. The study includes clinical evaluations of family history, radiological findings, histopathological examination of the skin, and genetic investigations.

Results: All affected individuals exhibited skin and mucosal lesions. Among the 15 cases, five (33%) showed neurological symptoms, four (26%) presented neuropsychiatric findings, and three (20%) had diabetes mellitus. We observed characteristic intracranial calcifications in all patients with epileptic seizures. Four out of the five cases with epilepsy and intracranial calcifications also had neuropsychiatric findings. All patients with neurological and neuropsychiatric findings had a frame-shift variant, but the same frame-shift variant was not associated with these findings in other individuals. In our study, no patient with variants other than frame-shift variants exhibited neurological or neuropsychiatric findings. Adrenal calcification, which was observed in 1 patient, was not previously linked to LP.

Conclusion: Our study observed diverse variations in LP cases among the Turkish population, with varying clinical presentation even among individuals with identical variations within the same family. In our series, the lack of correlation between genotype and phenotype makes providing specific genetic counseling to families challenging.

Introduction: Blended phenotypes resulting from the contribution of two or more genetic variants to the disease of a patient pose a significant diagnostic challenge. Correlating between the phenotypes and the genotypes of the affected patients is difficult in these cases, especially in the absence of a large family segregating the condition.

Case presentation: We report a child born to consanguineous Syrian parents with a complex phenotype including a skeletal dysplasia, characterized by a small thorax and phalangeal shortening, as well as cardiac anomalies and sensorineural hearing loss. Molecular analysis identified the presence of three potentially disease-causing genetic variants. These include homozygous variants in the IHH and TTC12B genes, known to be associated with acrocapitofemoral dysplasia (OMIM# 607778) and a form of short-rib thoracic dysplasia (OMIM# 613819), respectively, in addition to a heterozygous variant in the COL11A1 gene, associated with dominant forms of skeletal dysplasia, such as Marshall (OMIM# 154780) and Stickler (OMIM# 608481) syndromes, and hearing loss (OMIM# 618533).

Conclusion: We propose that the complex phenotype observed in the patient results from the contribution of l three of these variants. This case highlights some of the challenges encountered in the genetic counseling of families with rare genetic conditions.

Introduction: Charcot-Marie-Tooth (CMT) is a disorder that encompasses a group of hereditary neuropathies. The clinical features of CMT is variable due to genetic heterogeneity. This study aimed to evaluate the utility of targeted next-generation sequencing (NGS) panels in the molecular diagnosis of CMT in routine clinical practice and to determine the causative genetic variants.

Methods: NGS was used to detect the causative single nucleotide variants in 55 genes associated with CMT alongside multiplex ligation probe amplification (MLPA) for copy number variation (CNV) analysis of the PMP22 gene. The period from the first clinical findings to genetic testing was considered as the "diagnostic odyssey."

Results: A total of 58 patients with suspected CMT were analyzed. MLPA was performed on 54 patients, while 4 underwent direct NGS due to suspicion of other CMT types. MLPA revealed pathogenic CNVs in 21 patients (36.2%). Among the 33 patients with negative MLPA results, 24 underwent NGS. Pathogenic/likely pathogenic variants were identified in 17 (60.7%) of total 28 patients. Overall, the diagnostic yield was 65.5% (38/58). Moreover, a novel likely pathogenic variant (c.637C>T) was detected in the NDRG1 gene. The average diagnostic odyssey in diagnosed patients was 5.6 years.

Conclusion: Targeted NGS panels are a highly effective tool for the genetic diagnosis of CMT and increase the diagnostic rates when used in conjunction with MLPA. Molecular genetic diagnosis is critical for CMT patients, particularly in light of ongoing research into targeted therapies. Furthermore, presence of undiagnosed cases underscores the likelihood that additional causative genes and mechanisms in CMT etiology remain to be discovered.

Introduction: Mucopolysaccharidosis type IIIB is an autosomal recessive lysosomal disorder caused by variants in the α-n-acetylglucosaminidase (NAGLU) gene. It is a progressive neurodegenerative disorder with no treatment. Previous enzyme therapies have been unsuccessful. It is important to understand the mechanism of the disease to be able to find new treatments.

Methods: We did whole-exome sequencing and standard Sanger sequencing on 7 cases of four consanguineous families diagnosed with autism spectrum disorder.

Results: We identified two recurrent damaging biallelic Asp312Asn and p.Arg234Gly variants in the NAGLU gene. Structure modeling of these variants suggested that each variant affects the stability of the enzyme and results in a loss of activity. All affected individuals' enzymatic assay in leukocytes clearly showed that α-n-acetylglucosaminidase was completely inactive. Our patients underwent magnetic resonance imaging (MRI), revealing normal findings in two of them despite progressive clinical neurodegenerative symptoms. To our knowledge, these cases represent the second and third instances of normal MRI findings documented in the literature.