Molecular Syndromology最新文献

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.

Introduction: Prior research on the genotype and allele variations of immunometabolism genes and their correlations with the risk of myeloproliferative neoplasms (MPNs) and chronic myeloid leukemia (CML) is inconsistent.

Aim: This study aimed to assess the correlations between mutations in specific immunometabolism genes with the risk and progression of MPN and CML in Saudi patients.

Methods: This case-control study included 244 Saudi patients, 122 patients with MPNs and CMLs, and 122 healthy controls. Immunometabolism genes, including BCL3 (rs2927488 G>A), MDM4 (rs11801299 G>A), KLF14 (rs972283 G>A), and miR-146a (rs2910164 C>G), were identified via tetra amplification-refractory mutation system PCR.

Results: In comparison to healthy persons, MPN and CML patients exhibited a higher prevalence of genotype and allele variants in immunometabolism genes, BCL3 rs2927488 G>A (0.027), MDM4 rs11801299 G>A (0.028), KLF14 rs972283 G>A (0.0004), and miR-146a rs2910164 G>C (0.004).

Discussion and conclusion: The prevailing inheritance model suggested that mutations in all four immunometabolism genes were significantly correlated with an elevated chance of developing MPNs, with increases of 1.84-, 2-, 4.28-, and 2.75-fold for BCL3, MDM4, KLF14, and miR-146a, respectively, in comparison to healthy controls. In addition, we assessed the effect of gene polymorphisms on the course of the disease, and rapid disease progression was found to be correlated with the presence of these polymorphisms. These findings could help determine the risk of developing MPNs and patient prognosis.

[This corrects the article DOI: 10.1159/000540570.].

Introduction: RASopathies are genetic disorders linked to the RAS/MAPK signaling pathway, including Noonan syndrome and related conditions. These disorders have overlapping features and variable phenotypes, making diagnosis challenging. This study examines the clinical and genetic characteristics of RASopathies in pediatric patients to improve diagnostic accuracy and identify novel pathogenic variants.

Methods: A total of 23 patients, who were not related to each other and were clinically diagnosed with RASopathy, participated in the study. Patients underwent next-generation sequencing (NGS) panel analyses of 14 RASopathy genes.

Results: Pathogenic variants were found in 18 out of 23 patients (78%). The most common variants were in PTPN11 and SOS1. Novel variants were identified in KRAS and NF1 expanding the known genetic spectrum. Frequent clinical features included distinctive facial features, growth delays, and heart defects, notably pulmonary stenosis. Intellectual disability was more common in patients with PTPN11 variants, while SOS1 variants were associated with unique features such as previously unreported polydactyly and choanal atresia.

Conclusion: Targeted NGS panels improve diagnosis of RASopathies, with a variant detection rate of 78%. Including the NF1 gene, even without signs of neurofibromatosis, enhances diagnostic success. This study adds to our understanding of genotype-phenotype relationships in RASopathies and highlights new clinical features tied to SOS1 variants. Comprehensive genetic testing supports earlier and more personalized care for patients with RASopathies.

Introduction: Cobalamin J disease (CblJ) is an ultrarare autosomal recessive disorder of intracellular cobalamin metabolism associated with combined methylmalonic academia and homocystinuria (MAHCJ; 614857).

Case presentation: A new patient with MAHCJ, representing the eighth documented instance, is reported here. A novel homozygous missense variant c.1591C>T (p.Arg531Trp) in exon 17 of ABCD4 (NM_005050.4) was identified. The patient, a 15-year-old male of Azerbaijani descent, presented with severe abdominal pain beginning at the age of 1 year. These episodic pain attacks were accompanied by hypotonia, pallor, nausea, and vomiting. Initial evaluations were inconclusive. At the age of 8 years, the patient developed megaloblastic anemia due to vitamin B12 deficiency, leading to the initiation of replacement therapy. The pain attacks ceased during treatment but recurred whenever vitamin B12 levels dropped after discontinuation. The patient exhibited no dysmorphology, skin hyperpigmentation, somatic abnormalities, seizures, or neurodevelopmental delays and remains in remission with ongoing vitamin B12 treatment.

Discussion: This patient is the oldest diagnosed with MAHCJ and has the longest documented clinical course. This report expands the known clinical and molecular spectrum of this rare disease. We recommend remembering cobalamin defects in the differential diagnosis of unresolved abdominal pain attacks.

Introduction: Interstitial deletions in 3p21.31 are rare and have been associated with developmental delay, intellectual disability, and facial dysmorphism. To our knowledge, there are no reported individuals with a 3p21.31 interstitial deletion associated with aortic root dilatation.

Case presentation: We report a 2-year-old girl with 3p21.31p14.3 deletion, aortic root dilatation, global developmental delay, hypotonia, and distinctive facial features. The size of this interstitial deletion is 6.8 Mb and it encompasses 120 genes. None of these genes have a known association with aortic complications. A custom gene panel of 37 genes associated with familial thoracic aortic aneurysm did not identify a known monogenic cause of aortic dilatation in this individual.

Conclusion: This case represents an expansion of the phenotypic spectrum associated with 3p21.31 deletions, highlighting the novel association with aortic root dilatation. Further studies are needed to explore potential mechanisms linking this chromosomal deletion to vascular complications.