Molecular Syndromology最新文献

Introduction: Rubinstein-Taybi syndrome (RSTS) is most often caused by loss-of-function variants in CREBBP; intragenic duplications are rare and extremely under-recognized.

Case presentation: We describe a 5-year-old girl with global developmental delay, intellectual disability, frontal bossing, upslanted palpebral fissures, broad angulated halluces, and scoliosis. Whole-exome sequencing with copy number analysis revealed a heterozygous de novo duplication of approximately 13 kb encompassing exons 7-16 of CREBBP (NM_004380.3). Multiplex ligation-dependent probe amplification confirmed the duplication in the proband and excluded it in both parents. The event is predicted to introduce a frameshift, leading to premature truncation. No additional pathogenic variants were detected.

Conclusion: This is the first reported CREBBP duplication spanning exons 7-16, expanding the mutational spectrum of RSTS and illustrating that intragenic duplications can manifest with a partially atypical craniofacial profile. The case underscores the value of incorporating high-resolution copy number interrogation into RSTS workflows when single nucleotide variant analysis is uninformative and supports systematic deposition of such variants to refine genotype-phenotype correlations.

Introduction: Hyperekplexia is a rare non-epileptic paroxysmal disorder characterized by a marked startle response and hypertonia to auditory, tactile, or visual sudden external stimuli. GLRA1, SLC6A5, GLRB, and ATAD1 gene pathogenic variants have been identified in these patients.

Case report: The girl was born 39+1 weeks and admitted to the neonatal intensive care unit with spasm-like contractions and followed by breath holding. Except for transient hyperammonemia, neurologic and metabolic tests were normal, and there was no seizure-like movement during hospitalization. In the 4th month of her life, the patient had spasm-like findings with stimulation, and the symptoms were controlled with clonazepam, considering hyperekplexia. Clinical exome sequencing revealed a previously undescribed homozygous variant [c.748T>C; p.(Ser250Pro) in exon 4] in the SLC6A5 (NM_004211.5) gene. Sanger sequencing confirmed the c.748T>C variant in the family: both parents were heterozygous carriers, while the brother was homozygous. Her sibling also had stimulus-induced crying and stiffness in infancy, but these resolved within months without treatment, and his developmental milestones have been age-appropriate.

Conclusions: This case highlights the importance of recognizing hereditary hyperekplexia in the differential diagnosis of neonatal seizures and supports the potential pathogenic relevance of the SLC6A5 c.748T>C (p.Ser250Pro) variant, particularly in benign, nonrecurrent cases with transient hyperammonemia from catabolic stress and glycine transporter dysfunction.

Introduction: CRTAP-related osteogenesis imperfecta (OI) is a form of OI that ranges from moderate (type IV) to extremely severe (type II) and is caused by biallelic variants in the CRTAP gene. To date, only about 30 cases have been reported in the literature.

Methods: We describe two adults and one fetus with molecularly confirmed CRTAP-related OI.

Results: The phenotype varied extensively in terms of severity and clinical features, ranging from moderate (type IV) to severe (type III) and including cases with prenatal fractures as well as one case with a low number of fractures and no prenatal fractures. Interestingly, 1 patient presented with high myopia and bilateral retinal detachment, which have not been previously reported in OI type VII. Regarding molecular results, we identified three CRTAP variants that have not been previously reported in the literature. One of the variants was found in both a woman and an unrelated fetus of Cape Verdean descent, suggesting that the carrier frequency of this variant in the Cape Verde population may be relatively high.

Conclusion: We expand the clinical spectrum of patients with CRTAP variants and highlight the clinical variability of this extremely rare type of OI, which may present with either prenatal or postnatal onset. Our findings also underscore the importance of investigating the role of CRTAP in extra-skeletal tissues and assessing potential founder effects in underrepresented populations.

Introduction: Tyrosinemia type III is an extremely rare autosomal recessive metabolic disorder resulting from biallelic pathogenic mutations in the HPD 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 HPD 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.

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 ACTB or ACTG1 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 ACTB 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.

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.