Expanding the Phenotypic Spectrum of Alazami Syndrome: Two Unrelated Spanish Families.

Alazami syndrome is a rare disorder with an autosomal recessive inheritance caused by pathogenic biallelic variants in the LARP7 gene. Clinically, it is mainly characterized by short stature, intellectual disability, and dysmorphic facial features. However, the phenotype is not yet well-defined because less than 50 cases have been described to date. Here, we report three new patients from two unrelated Spanish families who, in addition to the defined features of Alazami syndrome, also exhibit unique features that broaden the phenotypic spectrum of the syndrome. Moreover, we describe the novel frameshift variant c.690_699delins27 in the LARP7 gene, in which loss of function is a known mechanism of Alazami syndrome.

A contingent model for cell-free DNA testing to detect fetal aneuploidy after first trimester combined screening.

OBJECTIVE: To assess the results of the first trimester combined test to design a prenatal protocol for the introduction of the cell-free fetal DNA test as a contingent screening model. METHOD: An observational retrospective study in 12,327 singleton pregnancies to analyze the results of the combined first trimester screening, the nuchal translucency ≥97.5 percentile, their cytogenetic results and birth outcomes. RESULTS: A total of 533 (4.3%) pregnant women had a risk in combined first trimester screening above 1/300. In this group, sixty nine had an unbalanced karyotype. The abnormal/normal karyotype ratio was 1/28 in pregnant women with intermediate risk (1/51-1/300) for trisomy 21 and trisomy 18, 1/58 with intermediate risk just for trisomy 21 and 1/37 with intermediate risk just for trisomy 18. A 19.8% of the unbalanced karyotypes had chromosomal abnormalities other than trisomies 21, 18 and 13. Two false negatives cases at first trimester combined screening presented a nuchal translucency ≥ p97.5th. CONCLUSION: We propose the introduction of the cell-free fetal DNA test when the risk of first trimester combined screening is intermediate (1/51-1/300) and when nuchal translucency is ≥ p97.5th with a low risk in the combined screening. This policy would allow us to continue to detect uncommon chromosomal abnormalities.

MECP2 Duplications in Symptomatic Females: Report on 3 Patients Showing the Broad Phenotypic Spectrum.

Xq28 microduplications including the MECP2 gene constitute a 100% penetrant X-linked syndrome in males caused by overexpression of normal MeCP2 protein. A small number of cases of affected females have been reported. This can be due to the location of the duplicated material into an autosome, but it can also be due to the location of the duplicated material into one of the X chromosomes and random or unfavorable skewed X chromosome inactivation, which is much more likely to occur but may be underdiagnosed because of the resulting broad phenotypic spectrum. In order to contribute to the phenotypic delineation of Xq28 microduplications including MECP2 in symptomatic females, the authors present clinical and molecular data on 3 patients illustrating the broad phenotypic spectrum. Our finding underlines the importance of quantitative analysis of MECP2 in females with intellectual disability and raises the question of the indication in females with borderline intellectual performances or learning difficulties.