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Genetic studies in Disorders of Sex Development ( DSD), representing a wide spectrum of developmental or functional conditions of the gonad, have mainly been oriented towards the coding genome. Application of genomic technologies, such as whole-exome sequencing, result in a molecular genetic diagnosis in ∼50% of cases with DSD. Many of the genes mutated in DSD encode transcription factors such as SRY, SOX9, NR5A1, and FOXL2, characterized by a strictly regulated spatiotemporal expression. Hence, it can be hypothesized that at least part of the missing genetic variation in DSD can be explained by non-coding mutations in regulatory elements that alter gene expression, either by reduced, mis- or overexpression of their target genes. In addition, structural variations such as translocations, deletions, duplications or inversions can affect the normal chromatin conformation by different mechanisms. Here, we review non-coding defects in human DSD phenotypes and in animal models. The wide variety of non-coding defects found in DSD emphasizes that the regulatory landscape of known and to be discovered DSD genes has to be taken into consideration when investigating the molecular pathogenesis of DSD. [ABSTRACT FROM AUTHOR]

Purpose To study the different genotypes and phenotypes in Belgian patients with albinism. Methods Phenotypes and genotypes in a cohort of 89 patients were studied in detail. These patients were then grouped according to genotype. Results A total of 40 patients with isolated oculocutaneous ( OCA), and 11 with XL ocular albinism ( XLOA) were molecularly confirmed. Nine syndromic OCA patients were identified. Genotypes of 29 patients were unknown at the time of study. Although not statistically significant due to small sample size, patients with a proper TYR mutation in combination with a temperature sensitive variant ( TS) generally showed milder characteristics. A study of one specific family showed 3 affected siblings with this genotype. However, 2 normal children, each of a different patient, also had this genotype. There was perfect concordance between fundoscopic identification of lyonization in 15 female carriers of XLOA, and molecular confirmation of heterozygosity. Two adult patients with Chediak-Higashi syndrome showed OCA in combination with neurodegeneration. Systemic abnormalities in 7 Hermansky-Pudlak syndrome patients were very variable. Conclusions Molecular analysis is essential to confirm clinical phenotyping in albinism. A causal relationship between a combination of a TYR mutation and the TS variant is as yet uncertain and requires more in depth analysis. [ABSTRACT FROM AUTHOR]

Purpose To investigate the accuracy of recognizing female heterozygotes for X-linked retinitis pigmentosa (XLRP) and choroideraemia (CHM) using fundoscopy and blue-light fundus autofluorescence ( FAF). Methods Retrospective analysis revealed 26 female XLRP heterozygotes from 17 different families (age 3-77 years) and 8 CHM heterozygotes from 5 families (age 14-65 years). Molecular diagnosis has been obtained for all subjects. Results In XLRP, 17 of 26 patients (65.4%) mentioned nyctalopia. RPGR mutations were identified in 18 subjects - 9 of which in ORF15 - whereas a causative mutation was found in RP2 in the remaining 8 subjects. Dilated fundoscopy showed no abnormalities in 8 subjects, a tapetoid reflex in 2, regional pigmentary changes in 16 and full-blown RP features in 2 patients. An abnormal FAF pattern was found in 18 of 26 patients (69.2%). Of the 26 molecularly proven heterozygotes, 23 (88.5%) showed abnormalities on fundoscopy and/or FAF. In CHM, only 1 of 8 patients - aged 40 - mentioned visual difficulties at night. In each of the 8 subjects, equatorial mottled pigmentary changes were evident. FAF revealed multiple hyper- and hypoautofluorescent flecks in all 8 patients. In both XLRP and CHM, clinical findings were independent of age or specific mutation. Conclusions Female heterozygotes of XLRP show abnormalities on dilated fundoscopy and/or blue-light fundus autofluorescence in 88.5% of cases with a molecularly proven diagnosis. The most characteristic feature is a radial pattern of alternating areas of hyper- and hypoautofluorescence. In CHM, all carriers exhibit pigmentary changes in the retinal midperiphery and scattered autofluorescence changes, despite a lack of visual symptoms. [ABSTRACT FROM AUTHOR]

Purpose To investigate the type and severity of colour vision deficiencies (CVDs) in Stargardt disease (STD). And, to establish how the degree of CVD relates to best‐corrected visual acuity (BCVA), full field ERG (ffERG) and duration of disease. Methods A retrospective, cross‐sectional study of 97 patients with a clinical diagnosis of STD included a comprehensive medical history and a full clinical work‐up, with extensive colour vision testing. Eight patients underwent anomaloscopy. ABCA4 was screened in 92 patients. Results Patients were allocated to 5 BCVA groups and to 3 ffERG groups. Normal colour vision was found in almost 30% of patients. R/G CVDs increased as BCVA declined. More than 50% had a deutan type R/G CVD, although protan R/G CVDs became progressively apparent as BCVA decreased. A predominance of pseudoprotanomaly was evident only on anomaloscopy. Additional Blue/Yellow (B/Y) CVDs were noted in 25% of patients. B/Y CVDs and BCVA higher than 0.75 were seen in adult‐onset STD. CVDs evolve to scotopization in patients with low BCVA and/or longstanding disease. Duration of disease did not correlate well with CVDs. Also, no statistically significant differences in ERG results were found between groups with or without a CVD. Conclusion Since colour vision function is better correlated to BCVA than either disease duration or ffERG, it is a rather reliable indicator of disease severity. The presence of CVDs may help to establish an early diagnosis of STD. [ABSTRACT FROM AUTHOR]

GATA2 deficiency, first described in 2011, is a bone marrow failure disorder resulting in a complex haematological and immunodeficiency syndrome characterised by cytopenias, severe infections, myelodysplasia and leukaemia. The only curative treatment is allogeneic haematopoietic stem cell transplantation (HSCT). Although knowledge on this syndrome has greatly expanded, in clinical practice many challenges remain. In particular, guidelines on optimal donor and stem cell source and conditioning regimens regarding HSCT are lacking. Additionally, genetic analysis of GATA2 is technically cumbersome and could easily result in false-negative results. With this report, we wish to raise awareness of these pitfalls amongst physicians dealing with haematological malignancies and primary immunodeficiencies., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

We present a family segregating for an autosomal dominant syndrome of hypotelorism, cleft palate/uvula, high-arched palate and mild mental retardation. Although these findings may suggest a form of holoprosencephaly, no holoprosencephaly was found on MRI of the proposita. Results of genetic studies were normal including FISH for deletion of 22q11, karyotype analysis, fragile X testing, high-resolution comparative genomic hybridization and SEPT9, SHH mutation analysis. The syndrome is reminiscent of the infrequently recognized autosomal dominant Schilbach-Rott syndrome.