Klinefelter variants, sex chromosome polysomy, pseudoautosomal region, complex psychological behavior, deteriorated brain development Klinefelter syndrome (KS) variants often share common features with classical syndrome but some of these variants present with a distinct phenotype. The incidence of sex chromosome tetrasomy and pentasomy are very less and generally diagnosed after prepubertal age. The early diagnosis of complex and unclassified syndromes and it's correlation with genotype is necessary for personalized treatment as well as genetic counselling of the affected families. We describe clinical presentation, and genetic diagnosis of two cases of variant KS. Our first case, a 4 year old male child presented with generalized tonic-clonic seizures (GTCSs), delayed milestones and dysmorphic features while case 2, a-21 years old male who had history of seizures and delayed puberty came to our lab for genetic diagnosis. The chromosomal analysis of case 1 and 2 showed 49,XXXXY and 48,XXYY karyotype respectively. The karyotype results were confirmed with fluorescence in situ hybridization (FISH) and array-CGH analysis. The FISH results were found to be consistent with karyotype but the array-CGH results showed the extra gain of region Yp11.2 in case 1 while the extra gain of region Xp22.33 in case 2. The cases were confirmed as variant KS on the basis of additional sex chromosomes and clinical presentation of deteriorated brain development. The present study suggests that the high doses of sex chromosome linked genes including pseudoautosomal region (PAR) caused the abnormal brain development. The combination of molecular techniques should be utilized for the diagnosis of such complex cases to understand the genotype-phenotype correlation and appropriate genetic counseling.
Background
Oculocutaneous albinism (OCA) is an autosomal recessive disorder characterized by hypo-pigmentation of skin, hair, and eyes. The OCA clinical presentation is due to a deficiency of melanin biosynthesis. Intellectual disability (ID) in OCA cases is a rare clinical presentation and appropriate diagnosis of ID is challenging through clinical examination. We report an Indian family with a rare co-inheritance of OCA1B and ID due to a novel TYR gene variant and chromosomal copy number variations.
Methods
We have done a study on three siblings (2 males and 1 female) of a family where all of them presented with hypopigmented skin, hair and eyes. The male children and their father was affected with ID. Targeted exome sequencing and multiplex ligation-dependent probe amplification analysis were carried out to identify the OCA1B and ID associated genomic changes. Further Array-CGH was performed using SurePrint G3 Human CGH + SNP, 8*60 K array.
Results
A rare homozygous deletion of exon 3 in TYR gene causing OCA1B was identified in all three children. The parents were found to be heterozygous carriers. The Array-CGH analysis revealed paternally inherited heterozygous deletion(1.9 MB) of 15q11.1-> 15q11.2 region in all three children. Additionally, paternally inherited heterozygous deletion(2.6 MB)of 10q23.2-> 10q23.31 region was identified in the first male child; this may be associated with ID as the father and the child both presented with ID. While the 2nd male child had a denovo duplication of 13q31.1-> 13q31.3 chromosomal region.
Conclusion
A rare homozygous TYR gene exon 3 deletion in the present study is the cause of OCA1B in all three children, and the additional copy number variations are associated with the ID. The study highlights the importance of combinational genetic approaches for diagnosing two different co-inherited disorders (OCA and ID). Hence, OCA cases with additional clinical presentation need to be studied in-depth forthe appropriate management of the disease.
The tyrosine kinase inhibitor (TKI) therapy has a high response rate in chronic myeloid leukemia (CML). However majority of patients relapse due to high mutation susceptibility of tyrosine kinase domain (TKD) of BCR/ABL fusion gene. We report a case of CML which was diagnosed and monitored for 10 years as per the ELN guidelines. Mutational analysis using Sanger sequencing (SS) and Next generation sequencing (NGS) and In-silico study was performed. The present case describes the acquisition pattern of TKD mutation against the TKIs (Imatinib, Dasatinib and Nilotinib) at different time points. Interestingly, NGS identified a dormant mutant clone with p.G250E mutation in 2019 which was first detected by SS in 2011 along with one novel mutation p. Ala287Thr, which likely explain the dormant nature of these mutant clones. Bioinformatics analysis (Modelling and docking) of novel variant revealed that mutation detected through deep sequencing technique reducing the IM efficacy by increasing inhibition constant and suggests higher concentration of IM to overcome such mutations. The study highlights the importance of NGS in CML, as it can detects clinically relevant low level mutant clones in CML patients.
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