Molecular Syndromology最新文献

Introduction: The aim of this study was to analyze the genotypic and clinical characteristics of Turkish patients with maturity-onset diabetes of the young (MODY) in Eastern Anatolia in order to improve the understanding of the genetic diversity and clinical manifestations of MODY. The findings should help to improve the diagnosis and management of monogenic diabetes.

Methods: This retrospective study included 279 patients with suspected MODY, selected for age at presentation, family history, no pancreas autoantibodies, and minimal/no need for insulin. A next-generation sequencing panel was used for genetic analysis. The panel included 15 different genes.

Results: Pathogenic variants were identified in 94% of the patients, with the majority being in GCK, HNF1A, and HNF4A. Variants in GCK were the most common (65%), followed by HNF1A (20%) and HNF4A (9%). Patients with GCK mutations exhibited mild fasting hyperglycemia, whereas HNF1A and HNF4A mutations were associated with progressive hyperglycemia.

Conclusion: This study provides significant insights into the genotypic and clinical spectrum of MODY within a Turkish population. The detection of pathogenic variants in genes such as GCK, HNF1A, and HNF4A underscores the importance of comprehensive genetic testing in patients suspected of MODY. The results emphasize the need for personalized approaches to optimize the diagnosis and treatment of MODY. Detailed genetic and clinical assessments play a pivotal role in identifying at-risk individuals and tailoring management strategies. These findings could guide the development of targeted therapies and enhance the clinical outcomes of patients with monogenic diabetes.

Introduction: The WDR81 gene is critically involved in autophagy, endosomal trafficking, and neurodevelopment. Pathogenic variants in this gene are associated with autosomal recessive disorders, such as cerebellar ataxia, intellectual disability, and disequilibrium syndrome. Despite recent advances, the full phenotypic spectrum remains incompletely characterized.

Case presentation: We report two female siblings carrying a homozygous missense variant in the WDR81 gene. The elder sister (age 15) presented with developmental regression, optic atrophy, motor neuropathy, and pes equinovarus. The younger sister (age 6) exhibited astigmatism, gait disturbance, and mild intellectual disability. Both were born to apparently non-consanguineous parents. Genetic testing confirmed the variant in both patients, and their clinical findings were compared with previously reported cases in the literature.

Conclusion: These cases expand the clinical spectrum of WDR81-related disorders. Our observations highlight the gene's central role in neurodevelopment and emphasize the need for further investigation into its diverse systemic effects.

Introduction: Lipodystrophy syndromes (LS) represent a clinically and genetically heterogeneous group of disorders of adipose tissue. LS are characterized by a partial or generalized deficiency of adipose tissue and variations in fat distribution throughout the body. Metabolic complications serve as significant determinants of morbidity and mortality in these syndromes.

Case presentation: The patient was assessed for general lipodystrophy and myopathy findings, and a CAVIN1 mutation was identified by next generation sequencing. Our patient exhibited low leptin and vitamin D levels, categorized as metabolic disorders, alongside increased insulin resistance. Additionally, low insulin-like growth factor 1 levels and delayed puberty were noted as hormonal disorders. Osteoporosis, scoliosis, ventricular extrasystoles, and ventricular tachycardia were observed as morbid conditions during the follow-up. We detected hypoplasia of the anterior cerebral artery and the internal carotid artery, which are seen as ultrarare. A coexistent structural cerebral vascular anomaly has not been previously reported in congenital generalized lipodystrophy type 4.

Conclusion: Congenital generalized lipodystrophy type 4 should be considered when associated with elevated liver enzyme levels and creatine phosphokinase values. Determining the underlying genetic cause enables an expeditious monitoring and treatment process.

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.