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The patient was in good clinical condition and did not experience recurrent infections after the start of Ig replacement therapy and antibiotic prophylaxis with amoxicillin until the age of 5 years, when he was admitted to a hospital with COVID-19 pneumonia requiring oxygen therapy for 4 days. Invasive infections with viruses, mycobacteria, parasites, and fungi have not been described in human MyD88 deficiency, although one patient had Bacillus Calmette-Guérin (BCG) adenitis after vaccination with BCG [[2], [5]]. We here present a patient carrying a homozygous deleterious mutation in I MYD88 i , who experienced viral infections and recurrent mucocutaneous candidiasis in addition to the classical invasive and superficial pyogenic infections. [Extracted from the article]

These patients and the patients reported by Lim et al. did not suffer from HSE or other severe viral infections, despite positive HSV serology in at least one patient, nor did our patient and her father, who is asymptomatic. Recently, Lim et al. described three unrelated children with influenza-related acute respiratory distress syndrome carrying the heterozygous loss of function I TLR3 i mutations P554S (dominant negative effect, two patients) and P680L (haploinsufficiency, one patient) [[3]]. TLR3 deficiency was also described in a patient suffering from recurrent HSV-triggered erythema multiforme and in patients suffering from severe influenza pneumonia [[2]]. [Extracted from the article]

DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils. [ABSTRACT FROM AUTHOR]

First, in HSV-associated EM, HSV-1 viral genes are expressed in intralesional keratinocytes and drive T helper 1-mediated inflammatory responses [[9]]. 1:CAS:528:DC%2BC3cXovFels7g%3D. 10.1074/jbc.M109.047464 9 Gober MD, Laing JM, Burnett JW, Aurelian L. The herpes simplex virus gene pol expressed in herpes-associated erythema multiforme lesions upregulates/activates SP1 and inflammatory cytokines. 1:CAS:528:DC%2BD2sXos1Kns7c%3D. 10.1159/000104259 10 Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component. [Extracted from the article]

Autosomal recessive IL-1R-associated kinase 4 (IRAK-4) deficiency is a rare cause of recurrent pyogenic infections with limited inflammatory responses. We describe an adult female patient with severe lung disease who was phenotypically diagnosed as suffering from autosomal dominant Hyper IgE syndrome (AD HIES) because of recurrent skin infections with Staphylococcus aureus, recurrent pneumonia and elevated serum IgE levels. In contrast to findings in AD HIES patients, no abnormalities were found in the Th17 and circulating follicular helper T cell subsets. A panel-based sequencing approach led to the identification of a homozygous IRAK4 stop mutation (c.877C > T, p.Gln293*). [ABSTRACT FROM AUTHOR]

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterised by skeletal dysplasia, exocrine pancreatic insufficiency and bone marrow failure. Various other conditions, such as hepatopathy and failure to thrive have been associated with SDS. A retrospective study was conducted to describe mutations, clinical features, and the immunological profile of 11 Belgian patients with genetically confirmed diagnosis of SDS. This study confirms the existing understanding of the classical features of SDS although the typical triad was present in only six out of nine fully studied patients. The following important observations are made in this cohort. Four out of eleven patients were misdiagnosed as having Asphyxiating Thoracic Dystrophy (Jeune syndrome) because of severe thoracic dystrophy. Another two patients presented with unexplained episodes of symptomatic hypoglycaemia. The immunological phenotype was heterogeneous although laboratory abnormalities were noticed in eight out of ten patients assessed. Three patients experienced a life threatening viral infection (respiratory syncytial virus, cytomegalovirus (CMV) and rotavirus). In one patient, CMV infection caused an episode of haemophagocytic lymphohistiocytosis. One patient has bronchiectasis at the age of 3 years due to recurrent respiratory tract infections. These findings strengthen the suspicion of an abnormal immune system in SDS. Liver anomalies, usually described as benign and transitory in SDS patients, were severe in two patients of the cohort. One patient developed hepatopulmonary syndrome. The findings in this national cohort of SDS patients could contribute to the prevention of misdiagnosis in the future and enable more rapid recognition of certain severe complications. [ABSTRACT FROM AUTHOR]

The validation and verification of laboratory methods and procedures before their use in clinical testing is essential for providing a safe and useful service to clinicians and patients. This paper outlines the principles of validation and verification in the context of clinical human molecular genetic testing. We describe implementation processes, types of tests and their key validation components, and suggest some relevant statistical approaches that can be used by individual laboratories to ensure that tests are conducted to defined standards. [ABSTRACT FROM AUTHOR]

Preimplantation genetic diagnosis (PGD) is now well established and provided in many European countries. However, regulations, professional standards and accreditation requirements can differ notably. Furthermore, no comprehensive independent data exist either about practice and provision in Europe or about the quality assurance practices and procedures designed to optimize the quality of the results. Consequently, a study was launched to obtain knowledge, currently lacking, of the provision and quality assurance of PGD services and cross-border activities in Europe. An online questionnaire was developed and sent to PGD providers, and expert opinions were obtained through interviews with professionals in specific countries. Information was gathered from 53 centres offering PGD in 17 European countries. There is a diverse array of tests available, with a trend for custom-made services. Although half of the centres have a designated quality manager, just 33% have achieved or are preparing for accreditation or certification. About 66% of the centres responded that they did not participate in external quality assessment, a problem exacerbated by the lack of existing PGD-specific schemes. Approximately 19% of the centres do not keep data on accuracy and 9% do not even follow up until birth. PGD is an expanding activity with an increasing international flow that accounts for approximately one-third of the activity reported. The survey highlights a significant need for improvement in quality assurance in PGD centres. On the positive side, important improvements in the quality management of these services are expected with the European Tissue Directive entering into force.European Journal of Human Genetics (2008) 16, 290–299; doi:10.1038/sj.ejhg.5201976; published online 19 December 2007 [ABSTRACT FROM AUTHOR]