Molecular Syndromology最新文献

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.

[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.

Introduction: Neurotrophic tyrosine receptor kinase 1 (NTRK1) encodes a 796 amino-acid-long transmembrane nerve growth factor (NGF) receptor, which is abundantly expressed in neuromuscular tissues. Deficiency of NTRK1 is typically clinically presented as autosomal recessive infantile congenital insensitivity to pain with anhidrosis (CIPA), characterized by decreased pain and temperature perception, anhidrosis, and, sometimes an intellectual disability and a premature death. So far, over 170 different NTRK1 mutations have been reported in the literature, including the missense disease-causing variants p.R748W.

Case presentation: In this case report, we present a 40-year-old man with CIPA based on the known and novel heterozygous p.R748W and c.575-15G>A NTRK1 mutation, respectively. This man exhibited progressive arthralgias, bursitis, folliculitis, fatigue, and pancreatitis with a slight variation of some immunological parameters that started about 3 years ago after vaccination.

Conclusion: The finding of an inflammatory autoimmune-like disease in the presented 40-year-old patient with a normal intelligence and a reduced sweating and pain sensation indicates that this phenotype represents, besides the typical serious infantile CIPA, a novel adult-onset clinical expression of the NTRK1-induced disease. In addition, the data here also support the recent suggestion that the defective NGF signaling of the neural, immune, and endocrine systems in CIPA may link this congenital disease to autoimmunity.

Introduction: Central hypothyroidism (CeH) is characterized by thyroid hormone deficiency due to impairment of pituitary thyroid stimulating hormone or hypothalamic TRH biosynthesis. It is extremely rare and affects approximately 1:16,000-100,000 individuals. Diagnosis, especially of isolated CeH, may be challenging. CeH is often seen as a part of multiple pituitary hormone deficiencies, but it can also be seen as isolated CeH. To date, some variants that can cause CeH have been identified, although in a number of patients the cause has not been clarified. Recently, variants of the insulin receptor substrate 4 (IRS4) gene have been reported to be the cause of isolated CeH. Herein, we report two related patients and their family with carriers with a novel X-linked frameshift variant in the IRS4 gene. It has also been shown that thyroid function may be slightly affected in the heterozygous female carriers in our study.

Case presentation: Herein, we reported two Turkish male patients with CeH due to a hemizygous variant in IRS4. The index case was a 15-year-and-2-month-old male who presented with a low serum-free thyroxin level, which was incidentally detected.

Conclusion: Isolated CeH should keep in mind in insistent low fT4 levels without an increase in thyroid stimulating hormone levels. Genetic testing can aid in identifying the underlying cause of CeH in such cases. This report demonstrates the significance of providing comprehensive laboratory and molecular features of the patients and carriers with the IRS4 variants.