Cytogenetic and molecular analysis of distal 4q duplication with distinctive phenotype using single-nucleotide polymorphism array

Aims There is little knowledge about partial trisomy 4q and the genotype–phenotype correlation. In this study, we presented the detail of two Chinese families with partial distal 4q duplication in an attempt to clarify the correlation between the genotype and the phenotype. Methods Two pedigrees with distal 4q duplication were enrolled in this study. Karyotype analysis and single-nucleotide polymorphism (SNP) array detection were performed for prenatal diagnosis. Fluorescence in situ hybridization analysis. (FISH) was conducted to verify the copy number variants. Results Two families with partial trisomy 4q were identified. The fetus in pedigree 1 exhibited multiple ultrasound anomalies including intrauterine growth restriction and an atrioventricular septal defect who had a duplication of 4q28.3-qter associate with 6p25.2-p25.3 deletion, which resulted from balanced translocation carried by his father t(4;6)(q28.3;p25.2). The fetus in pedigree 2 had a distal 4q28.3-qter duplication combined with monosomy of Xp21.3-p22.3, and the karyotype was described as 46,X,der(X)t(X;4)(p21.3;q28.3)mat, which originally inherited from the pregnant woman who exhibited a mild clinical phenotype limited to short stature. Conclusions In our study, we for the first time identified the partial trisomy 4q associate with 6p or Xp deletion. In addition, our finding further strengthens that mild clinical phenotype in 4q duplication case may be due to the spreading of X inactivation to the autosomal in derivation of chromosome X.

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus

Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics have not been reported. Here, we determine the major oncogenic events in PTC from non-exposed Belarusian children and assess their clinicopathological correlations. Among the 34 tumors, 23 (67.6%) harbored one of the mutually exclusive oncogenes: 5 (14.7%) BRAFV600E, 4 (11.8%) RET/PTC1, 6 (17.6%) RET/PTC3, 2 (5.9%) rare fusion genes, and 6 (17.6%) ETV6ex4/NTRK3. No mutations in codons 12, 13, and 61 of K-, N- and H-RAS, BRAFK601E, or ETV6ex5/NTRK3 or AKAP9/BRAF were detected. Fusion genes were significantly more frequent than BRAFV600E (p = 0.002). Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAFV600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC in Belarus largely parallels that in Chernobyl PTC, yet the frequencies of some oncogenes may likely differ from those in the early-onset Chernobyl PTC; clinicopathological features correlate with the oncogene type.

Genetic and Clinical Phenotypic Analysis of Familial Stapes Sclerosis Caused by a NOG Mutation

Background：Noggin protein encoded by NOG gene can interfere with the binding of bone morphogenetic protein to its receptor, thus affecting bone and joint develop pment. The symptoms include abnormal skeletal development and conductive deaf ness Methods: In a Retrospective study, clinical data of the proband and her family members include 8 people and 50 healthy normal controls were collected. Secon d-generation sequencing were performed on peripheral blood samples from them. Results：The sequencing analysis indicated that, in the probrand, the NOG gene included c.532T>C (cytosine deletion), leading to an amino acid change. The prob and's father, grandmother, second sister, and third sister also had this mutation, whereas those with normal phenotypes did not have the mutation. Conclusion：Analysis of this family showed that the new presentation of c.532T>C mutation in the NOG gene resulted in syndrome-type autosomal dominant inheritan ce reflected in a mild clinical phenotype, which is of great significance for further studies of the clinical phenotype and pathogenesis of stapetectopia.

Delayed-onset adrenal hypoplasia congenita and hypogonadotropic hypogonadism caused by a novel mutation in DAX1

In this study, we described a male who presented with delayed-onset adrenal hypoplasia congenita (AHC) and mild hypogonadotropic hypogonadism (HHG) without a relevant family history. A novel mutation in the DAX1 (dosage-sensitive sex reversal, congenital adrenal hypoplasia critical region on the X chromosome, gene 1) gene was shown to cause X-linked AHC and HHG. Genetic analysis revealed a novel nonsense mutation, c.154G > T (p.Glu52Term), in the DAX1 gene. Molecular testing demonstrated that the milder phenotype caused by this mutation was due to expression of a partially functional, amino-truncated DAX1 protein generated from an alternate in-frame translation start site (methionine at codon 83). This unusual case revealed a potential mechanism for a novel mutation that resulted in an unusual delayed-onset mild clinical phenotype. It expands the spectrum of adrenal hypoplasia congenita and hypogonadotropic hypogonadism.

Compound heterozygous LPIN2 pathogenic variants in a Majeed Syndrome patient with recurrent fever and severe neutropenia: case report

Background Majeed syndrome is a rare, autosomal recessive autoinflammatory disorder first described in 1989. The syndrome starts during infancy with recurrent relapses of osteomyelitis typically associated with fever, congenital dyserythropoietic anemia (CDA) and often neutrophilic dermatosis. Mutations in the LPIN2 gene located on the short arm of chromosome 18 have been identified as being responsible for the Majeed syndrome. Case presentation We report a 8-month old boy, who presented with recurrent fever, mild to moderate anemia and severe neutropenia. Erythrocyte sedimentation rate and C-reactive protein were elevated. Molecular studies identified a paternal splicing donor site variant c.2327+1G>C and a maternal frameshift variant c.1691_1694delGAGA (Arg564Lysfs*3)in LPIN2. Conclusions Up to now, only a few cases with LPIN2 mutation have been reported, mainly in the Middle East with homozygous variants. Our patient exhibited a mild clinical phenotype and severe neutropenia, distinct from previously reported.