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X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by pathogenic variants in the BTK gene, resulting in impaired B cell differentiation and maturation. Over 900 variants have already been described in this gene, however, new pathogenic variants continue to be identified. In this report, we describe 22 novel variants in BTK, associated with B cell deficiency with hypo- or agammaglobulinemia in male patients or in asymptomatic female carriers. Genetic data was correlated with BTK protein expression by flow cytometry, and clinical and family history to obtain a comprehensive assessment of the clinico-pathologic significance of these new variants in the BTK gene. For one novel missense variant, p.Cys502Tyr, site-directed mutagenesis was performed to determine the impact of the sequence change on protein expression and stability. Genetic data should be correlated with protein and/or clinical and immunological data, whenever possible, to determine the clinical significance of the gene sequence alteration., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Androgen insensitivity syndrome (AIS) is a rare X-linked disorder due to mutations in the androgen receptor ( AR ) gene causing end-organ resistance to the androgenic hormone., Subjects and Methods: Genetic studies were carried out in two families by karyotype and targeted exome sequencing of the AR gene., Results: Two novel missense mutations were identified, p.L822P and p.P392S, in two families with complete androgen insensitivity (CAIS) and partial androgen insensitivity (PAIS), respectively. Both had 46, XY karyotype. The mother was a heterozygous carrier in PAIS and negative in CAIS. These two were novel mutations, reported for the first time, in the AR gene. In silico analysis predicted that both mutations were damaging. We reviewed the various reported Indian mutations in the AR gene., Conclusion: AR gene mutations cause a wide spectrum of disorders from CAIS to male infertility or primary amenorrhea. Early diagnosis is essential for gender assignment and further management, family counseling, and prenatal diagnosis., Competing Interests: There are no conflicts of interest.

Background: Androgen insensitivity syndrome or testicular feminization syndrome is a rare X-linked recessive disorder, which encompasses a wide range of phenotypes that are caused by numerous different mutations in the androgen receptor gene. Complete androgen insensitivity syndrome occurs when the body cannot use androgens at all. People with this form of the condition have the external sex characteristics of females, but do not have a uterus and therefore do not menstruate and are unable to conceive a child (infertile)., Methods: In this paper, we report three cases of familial complete androgen insensitivity syndrome who presented with primary amenorrhea., Results: Physical examination, ultrasonography studies, and biochemical, karyotype, and molecular cytogenetic analyses were conducted. Based on the findings, they were diagnosed and confirmed as having complete androgen insensitivity syndrome., Conclusion: A multidisciplinary team is needed from disclosure of the diagnosis, gender assignment, surgical management, hormonal replacement therapy, to counseling and support., Competing Interests: The authors declare that there is no conflict of interest. Informed consent Informed consent was obtained from all individual participants included in the study. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standard of the Institutional research/ethics committee.

Becker muscular dystrophy (BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed.

Persons with unexplained early-onset stroke have been targeted for screening surveys for Fabry disease, the most common of the three X-linked lysosomal disorders, because Fabry patients with stroke are more likely to have the life-threatening progressive cardiac and renal manifestations and would therefore most benefit from early diagnosis and intervention with enzyme replacement therapy (ERT). Among 175 Israeli patients with unexplained cryptogenic stroke screened for mutations in the Fabry α galactosidase A (GLA) gene, sequencing identified six with 2-4 GLA intronic variants, one of whose father and three sisters had the same variants. Two variants, c.640-16A>G (g.10115A>G) in intron 4 and c.1000-22C>T (g.10956C>T) in intron 6, were common to all patients. However, three males with a common four variant intronic haplotype had low residual enzyme activity and ~50% reduced mRNA expression. Transcript splice-site defects were not identified in any of the index cases and X-chromosome inactivation was not highly skewed in the six females. These data do not suggest that GLA intronic variants, per se, are pathogenic. Nonetheless, it is clear that a certain intronic haplotype in males with cryptogenic stroke is associated with reduced GLA expression and function., (Copyright © 2014 Elsevier B.V. All rights reserved.)