Methods:Patients referred for cystic fibrosis screening from January 2005 through December 2010 were tested using either a 32-mutation panel (n = 1,601,308 individuals) or a 69-mutation panel (n = 109,830). Results:The carrier frequencies observed for the 69-mutation panel study population (1/36) and Caucasian (1/27) and African-American individuals (1/79) agree well with published cystic fibrosis carrier frequencies; however, a higher carrier frequency was observed for Hispanic-American individuals (1/48) using the 69-mutation panel as compared with the 32-mutation panel (1/69). The 69-mutation panel detected ~20% more mutations than the 32-mutation panel for both African-American and Hispanic-American individuals. Conclusion:Expanded panels using race-specific variants can improve cystic fibrosis carrier detection rates within specific populations. However, it is important that the pathogenicity and the relative frequency of these variants are confirmed. Genet Med advance online publication 19 December 2013

The data indicate that multiplex ligation-dependent probe amplification is a sensitive and rapid method to identify PKHD1 deletions. Our study demonstrates that dosage analysis will increase the PKHD1 mutation detection rate and should be performed as a complementary assay in patients suspected to have ARPKD in the absence of two clear pathogenic mutations.

Uniparental disomy is a genetic cause of disease that may result in the inheritance of an autosomal recessive condition. A child with developmental delay and hypotonia was seen and found to have severely abnormal myelination. Lysosomal enzyme testing identified an isolated deficiency of beta-galactosidase. Subsequently, homozygous missense mutations in the galactosidase, beta 1 (GLB1) gene on chromosome 3 were found. Parental testing confirmed inheritance of two copies of the same mutated maternal GLB1 gene, and no paternal copy. SNP analysis was also done to confirm paternity. The patient was ultimately diagnosed with autosomal recessive GM1 gangliosidosis caused by maternal uniparental isodisomy. We provide a review of this patient and others in which uniparental disomy (UPD) of a non-imprinted chromosome unexpectedly caused an autosomal recessive condition. This is the first case of GM1 gangliosidosis reported in the literature to have been caused by UPD. It is important for genetic counselors and other health care providers to be aware of the possibility of autosomal recessive disease caused by UPD. UPD as a cause of autosomal recessive disease drastically changes the recurrence risk for families, and discussions surrounding UPD can be complex. Working with families to understand UPD when it occurs requires a secure and trusting counselor-family relationship.

Rett syndrome is a dominant X-linked disorder caused by point mutations (approximately 80%) or by deletions or insertions (approximately 15% to 18%) in the MECP2 gene. It is most common in females but lethal in males, with a distinctly different phenotype. Rett syndrome patients have severe neurological and behavioral problems. Clinical genetic testing laboratories commonly use characterized genomic DNA reference materials to assure the quality of the testing process; however, none are commercially available for MECP2 genetic testing. The Centers for Disease Control and Prevention's Genetic Testing Reference Material Coordination Program, in collaboration with the genetic testing community and the Coriell Cell Repositories, established 27 new cell lines and characterized the MECP2 mutations in these and in 8 previously available cell lines. DNA samples from the 35 cell lines were tested by eight clinical genetic testing laboratories using DNA sequence analysis and methods to assess copy number (multiplex ligation-dependent probe amplification, semiquantitative PCR, or array-based comparative genomic hybridization). The eight common point mutations known to cause approximately 60% of Rett syndrome cases were identified, as were other MECP2 variants, including deletions, duplications, and frame shift and splice-site mutations. Two of the 35 samples were from males with MECP2 duplications. These MECP2 and other characterized genomic DNA samples are publicly available from the NIGMS Repository at the Coriell Cell Repositories.

Since the declaration of SARS-CoV-2 outbreak as a pandemic, the United Arab Emirates (UAE) public health authorities have adopted strict measures to reduce transmission as early as March 2020. As a result of these measures, flight suspension, nationwide RT-PCR and surveillance of viral sequences were extensively implemented. This study aims to characterize the epidemiology, transmission pattern, and emergence of variants of concerns (VOCs) and variants of interests (VOIs) of SARS-CoV-2 in the UAE, followed by the investigation of mutations associated with hospitalized cases. A total of 1274 samples were collected and sequenced from all seven emirates between the period of 25 April 2020 to 15 February 2021. Phylogenetic analysis demonstrated multiple introductions of SARS-CoV-2 into the UAE in the early pandemic, followed by a local spread of root clades (A, B, B.1 and B.1.1). As the international flight resumed, the frequencies of VOCs surged indicating the January peak of positive cases. We observed that the hospitalized cases were significantly associated with the presence of B.1.1.7 (p < 0.001), B.1.351 (p < 0.001) and A.23.1 (p = 0.009). Deceased cases are more likely to occur in the presence of B.1.351 (p < 0.001) and A.23.1 (p = 0.022). Logistic and ridge regression showed that 51 mutations are significantly associated with hospitalized cases with the highest proportion originated from S and ORF1a genes (31% and 29% respectively). Our study provides an epidemiological insight of the emergence of VOCs and VOIs following the borders reopening and worldwide travels. It provides reassurance that hospitalization is markedly more associated with the presence of VOCs. This study can contribute to understand the global transmission of SARS-CoV-2 variants.