Molecular Syndromology最新文献

Introduction: In this study, we examined the genotype-phenotype characteristics of the cases with pathogenic/possibly pathogenic variants in the RYR1 gene that we follow in our clinic.

Methods: Data of patients who applied to our clinic and had pathogenic/possibly pathogenic/variant of unknown significance variants in the RYR1 gene were evaluated retrospectively. Patients were examined in terms of demographic, clinical, and individual genetic data, age of symptom-onset, sex, clinical features, clinical types, variants, cardiac involvement, muscle biopsy results, serum creatinine kinase (CK) levels, family history, and consanguinity.

Results: The variants were detected in 19 patients from 18 different families. The most common (n = 5, 38.4%) variant was the c.7880T>G (p.Val2627Gly) heterozygous change. 63.1% of our patients were male (n = 12) and 37.9% were female. Admission complaints included a floppy baby, developmental delay, or hyperCKemia. The most common clinical spectrum was malignant hyperthermia (MH) sensitivity (n = 8, 44.4%). We also identified four novel variants in our cohort.

Conclusion: RYR1 is known to be the gene most associated with MH. It is very important to manage and take precautions against possible comorbidities and anesthesia complications. For this reason, we think that RYR1 analyses should be given priority in the diagnostic algorithm.

Introduction: Opsismodysplasia (OPS) is a rare skeletal dysplasia characterized by delayed bone maturation, distinctive skeletal deformities, and severe growth impairment. Mutations in the INPPL1 gene, particularly homozygous variants, are the primary genetic cause of this condition. While bisphosphonate therapy has shown efficacy in OPS cases with hypophosphatemic rickets, its role in cases without this complication remains unclear.

Case presentation: A 2-year-and-2-month-old girl with OPS was treated with intravenous pamidronate (0.5 mg/kg/3 months). Initial evaluations showed severe short stature and low bone mineral density (DEXA SDS: -3.16). After three courses of treatment, the patient achieved independent walking, and her DEXA SDS improved to -2.5 over 1 year.

Discussion: Pamidronate is effective in treating OPS even in the absence of hypophosphatemic rickets, showing potential as a therapeutic option for this rare condition.

Introduction: GATAD2B-associated neurodevelopmental disorder (GAND) is caused by pathogenic variants in GATAD2B which encodes p66beta, a subunit of a transcription repressor. The main presentations of GAND are intellectual disability, speech impairment, and dysmorphism. However, these features overlap with other neurodevelopmental syndromes and are not specific enough to be recognised for a particular clinical diagnosis without molecular confirmation.

Methods: Macrocephaly was detected prenatally and at birth. Postnatal brain MRI also revealed ventriculomegaly. Chromosomal microarray analysis and metabolites in plasma, serum, or urine were investigated due to microcephaly and dysmorphism, and all results were normal. Next-generation sequencing using a targeted gene panel did not identify any pathogenic variant. Exome sequencing was subsequently performed.

Results: A heterozygous single nucleotide deletion in exon 5 of GATAD2B (p.His216Metfs*24) was detected and Sanger validated. Targeted Sanger sequencing of parental samples showed that it is de novo.

Conclusion: We describe the first patient with GAND from Southeast Asia with Korean-Chinese parentage. The identification of a pathogenic variant in GATAD2B clarifies her diagnosis and adds to the genotypic and phenotypic spectrum of this disorder. This report illustrates the use of genetic testing to obtain a definite diagnosis.

Introduction: Newborn screening program enable pre-symptomatic detection patients with severe forms of T and B cell immunodeficiency. Despite the high prevalence of 22q11.2 deletion syndrome, only 1 in 10 patients develop lymphopenia that can be detected by newborn screening program. This report presents a unique familial case of 22q11.2 deletion syndrome and Wiskott-Aldrich syndrome, highlighting the importance genetic counseling and a detailed analysis of the family history.

Case presentation: The article presents a case of the two rare genetic diseases in patients from the same family: 22q11.2 deletion syndrome in one and Wiskott-Aldrich syndrome in the other. Both diseases belong to the group of combined immunodeficiencies with syndromic features and are potentially life-threatening conditions requiring follow-up by a wide range of specialists: immunologists, geneticists, cardiologists, endocrinologists, and medical psychologists.

Conclusion: Our work aimed to describe the clinical manifestations, genetic characteristics, and diagnosis of these disorders. It is worth emphasizing that the timely diagnosis of not only 22q11.2 deletion syndrome but also other primary immunodeficiencies in the Russian Federation became possible due to the introduction of extended neonatal screening into widespread practice. For such patients, comprehensive early interventional treatment and follow-up by a wide range of specialists is important to improve prognosis and quality of life.

[This corrects the article DOI: 10.1159/000540925.].

Introduction: TRIO-associated neurodevelopmental disorders are rare genetic conditions caused by pathogenic variants in the TRIO gene, which plays a crucial role in neuronal development. Mutations in the TRIO gene are increasingly associated with autosomal dominant inheritance. However, de novo occurrences in dizygotic twins remain rare and poorly understood.

Case presentation: In this work, clinical exome sequencing (CES) was performed on dizygotic twin sisters who presented with neurodevelopmental delay, intellectual disability, behavioral issues, and microcephaly. Segregation analysis using conventional Sanger sequencing was conducted on the parents to assess the inheritance pattern. A pathogenic missense variant c.4283G>A (p.Arg1428Gln) in the GEFD1 domain of the TRIO gene was identified. This variant is known to reduce GEF activity toward Rac1, impacting neuronal signaling pathways. Segregation analysis did not detect the variant in the parents, and mosaicism remains a possibility that could not be fully ruled out due to the limitations of this technique. Despite the lack of a definitive molecular diagnosis in the parents, detailed genetic counseling was provided to the family.

Conclusion: These findings highlight the diagnostic value of CES in rare neurodevelopmental disorders and suggest a plausible but unproven parental germline or early postzygotic mosaic event, while acknowledging alternative explanations.

Introduction: Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH) is a rare genetic condition caused by heterozygous pathogenic variants in the RERE gene, which encodes a transcriptional co-repressor essential for embryonic development. Most reported cases result from de novo variants and show a broad spectrum of neurodevelopmental and structural abnormalities. This report expands the phenotypic spectrum of NEDBEH by describing the first association with a Chiari type I malformation.

Case presentation: We report a 26-year-old Colombian male presenting with global developmental delay, progressive spasticity, mild dysmorphic features and a Chiari type I malformation, a finding not previously linked to RERE variants. Whole-exome sequencing identified a heterozygous de novo missense variant in RERE (NM_001042681.3:c.815A>G; p.Tyr272Cys), initially classified as a variant of uncertain significance but supported as likely pathogenic according to ACMG criteria (PP3, PM2). The RERE gene functions as a retinoic acid-dependent transcriptional cofactor, a pathway critical for hindbrain segmentation and morphogenesis, providing a plausible mechanism for the cerebellar anomaly observed.

Conclusion: This case broadens the clinical spectrum of RERE-related NEDBEH, suggesting potential cerebellar involvement secondary to disrupted retinoic acid signaling. It emphasizes the importance of genomic testing for patients with neurodevelopmental delay and structural brain malformations, enabling accurate diagnosis, genetic counseling, and deeper understanding of rare developmental disorders.

Introduction: Incontinentia pigmenti and CHILD syndrome are genodermatoses characterized by an X-linked dominant inheritance pattern, resulting from pathogenic variants in the IKBKG and NSDHL genes, respectively.

Methods: This study examines 3 pediatric patients exhibiting a compatible phenotype with inconclusive genetic studies, aiming to evaluate the diagnostic utility of optical genome mapping (OGM) in detecting alterations that could elucidate these conditions.

Results: The identified structural variants consisted of deletions of varying sizes in the Xq28 cytoband, encompassing regions that contain exons.

Conclusion: OGM demonstrates advantages over other techniques for identifying structural variants. This observation highlights how advancements in cytogenomics enhance the resolution with which cases previously inaccessible through conventional cytogenetics can now be investigated.

Introduction: Kenny-Caffey syndrome type 2 (KCS2, #OMIM127000) is an extremely rare skeletal dysplasia characterized by characteristic facial features, relative macrocephaly, short stature, hypoparathyroidism, hypocalcemia, cortical thickening of tubular bones, and medullary stenosis. It is caused by the Family with Sequence Similarity 111 Member A (FAM111A) gene.

Case presentation: Herein, we report a 7-year-old boy with microphthalmia, delayed anterior fontanelle closure, short stature, hypoparathyroidism, hypocalcemia, cortical thickening of tubular bones, and medullary stenosis. The presented patient had microcephaly, maculopathy, and craniosynostosis as rare distinct features. Microtia, lacunar skull appearance, and Arnold-Chiari malformation were present only in the reported patient. A diagnosis of KCS2 was considered with the clinical and radiological findings. Whole-exome sequencing identified a heterozygous pathogenic hotspot variant, c.1706G>A p.Arg569His (NM_001312909.2), in the FAM111A gene.

Conclusion: Accurate diagnosis plays a critical role in enhancing clinical awareness, improving patient management, and offering appropriate genetic counseling for affected families.

Introduction: Parenti-Mignot neurodevelopmental syndrome is caused by pathogenic variants of the CHD5 gene - involved in brain development - and is characterized by developmental delay, intellectual disability, and behavioral disturbances (i.e., autism spectrum disorder or related social problems, obsessive-compulsive tendencies, and aggressive behavior) as well as subtle facial dysmorphisms, epilepsy, hypotonia, and craniosynostosis. To date, cognition, behavior, and psychopathology in patients are either scarcely studied (in children, adolescents, and young adults) or not studied at all. Therefore, this case report aimed to provide additional insights into the cognitive and behavioral phenotype of Parenti-Mignot neurodevelopmental syndrome and discuss possibilities for support and treatment.

Case presentation: This study presents the case of a 54-year-old male with Parenti-Mignot neurodevelopmental syndrome (nonsense variant in the CHD5 gene), who struggles with mood problems and aggressive behaviors. Intelligence, cognitive functioning, and psychopathology are described by using neuropsychological assessment. Moderate to mild intellectual disability was found. Levels of adaptive functioning and performance on measures of attention, executive functioning, and memory were within the expected range considering intelligence level, whereas social cognition constituted a weakness within the profile. Additionally, results indicated internalizing and externalizing behavioral problems and deficits in emotion regulation skills.

Conclusion: It is hypothesized that behavioral disturbances of patients with the Parenti-Mignot neurodevelopmental syndrome are likely to result from an underlying cognitive profile that is characterized by low intelligence, social cognitive impairments, and poor emotion regulation. CHD5 involvement in cortical brain development may be an explanation for these cognitive deficits. In clinical practice, neuropsychological assessment can provide helpful pointers for treatment and support in daily functioning.