Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements.

Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities. We found that the rearrangements predict disruption of long-range chromatin interactions between several enhancers and genes whose annotated clinical features are strongly associated with the subjects' phenotypes. We confirm gene-expression changes for a couple of candidate genes to exemplify the utility of our analysis of position effect. These results highlight the important interplay between chromosomal structure and disease and demonstrate the need to utilize chromatin conformational data for the prediction of position effects in the clinical interpretation of non-coding chromosomal rearrangements.

Phenotypic heterogeneity of genomic disorders and rare copy-number variants.

BACKGROUND: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS: We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS: Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02). CONCLUSIONS: Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).

Identification of uncommon recurrent Potocki-Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in PTLS.

Nonallelic homologous recombination (NAHR) can mediate recurrent rearrangements in the human genome and cause genomic disorders. Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are genomic disorders associated with a 3.7 Mb deletion and its reciprocal duplication in 17p11.2, respectively. In addition to these common recurrent rearrangements, an uncommon recurrent 5 Mb SMS-associated deletion has been identified. However, its reciprocal duplication predicted by the NAHR mechanism had not been identified. Here we report the molecular assays on 74 subjects with PTLS-associated duplications, 35 of whom are newly investigated. By both oligonucleotide-based comparative genomic hybridization and recombination hot spot analyses, we identified two cases of the predicted 5 Mb uncommon recurrent PTLS-associated duplication. Interestingly, the crossovers occur in proximity to a recently delineated allelic homologous recombination (AHR) hot spot-associated sequence motif, further documenting the common hot spot features shared between NAHR and AHR. An additional eight subjects with nonrecurrent PTLS duplications were identified. The smallest region of overlap (SRO) for all of the 74 PTLS duplications examined is narrowed to a 125 kb interval containing only RAI1, a gene recently further implicated in autism. Sequence complexities consistent with DNA replication-based mechanisms were identified in four of eight (50%) newly identified nonrecurrent PTLS duplications. Our findings of the uncommon recurrent PTLS-associated duplication at a relative prevalence reflecting the de novo mutation rate and the distribution of 17p11.2 duplication types in PTLS reveal insights into both the contributions of new mutations and the different underlying mechanisms that generate genomic rearrangements causing genomic disorders.

Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the National Society of Genetic Counselors.

The 1997 discovery of free fetal DNA in maternal plasma launched clinical researchers' efforts to establish a reliable method for non-invasive prenatal testing for fetal genetic conditions. Various methods, including, but not limited to, massively parallel sequencing (MPS) and selective analysis of cell-free fetal DNA in maternal plasma, have recently been developed as highly sensitive and specific noninvasive screening tools for common fetal chromosome aneuploidies. Incorporating these new noninvasive technologies into clinical practice will impact the current prenatal screening paradigm for fetal aneuploidy, in which genetic counseling plays an integral role. The National Society of Genetic Counselors (NSGC) currently supports Noninvasive Prenatal Testing/Noninvasive Prenatal Diagnosis (NIPT/NIPD) as an option for patients whose pregnancies are considered to be at an increased risk for certain chromosome abnormalities. NSGC urges that NIPT/NIPD only be offered in the context of informed consent, education, and counseling by a qualified provider, such as a certified genetic counselor. Patients whose NIPT/NIPD results are abnormal, or who have other factors suggestive of a chromosome abnormality, should receive genetic counseling and be given the option of standard confirmatory diagnostic testing.

Balanced information about Down syndrome: what is essential?

The purpose of this study was to explore the perspectives of genetic counselors and parents of children with Down syndrome to define essential information for the initial discussion of a new diagnosis. We compared information given in both prenatal and postnatal settings, and also aimed to distinguish differences between the informational needs of parents and the information genetic counselors provide. Online surveys were distributed to members of the National Down Syndrome Congress, National Down Syndrome Society, and National Society of Genetic Counselors. Participants included 993 parents of children with Down syndrome and 389 genetic counselors. Participants rated 100 informational features about Down syndrome as Essential, Important, or Not Too Important for inclusion in the first discussion of the diagnosis. Responses identified 34 essential informational items for the initial discussion of Down syndrome, including clinical features, developmental abilities, a range of prognostications, and informational resources. Healthcare providers should consider incorporating these items in their initial discussion of a diagnosis in both prenatal and postnatal settings. Statistically significant differences between parent and genetic counselor responses illustrate that information is valued differently and that parents appreciate information about the abilities and potential of people with Down syndrome, as opposed to clinical details. Balancing clinical information with other aspects of the condition, as well as a better understanding of the information parents consider most important, may enable healthcare professionals to more effectively satisfy families' informational needs following a new diagnosis of Down syndrome.

Practice guidelines for communicating a prenatal or postnatal diagnosis of Down syndrome: recommendations of the national society of genetic counselors.

Down syndrome is one of the most common conditions encountered in the genetics clinic. Due to improvements in healthcare, educational opportunities, and community inclusion over the past 30 years, the life expectancy and quality of life for individuals with Down syndrome have significantly improved. As prenatal screening and diagnostic techniques have become more enhanced and widely available, genetic counselors can expect to frequently provide information and support following a new diagnosis of Down syndrome. This guideline was written for genetic counselors and other healthcare providers regarding the communication of a diagnosis of Down syndrome to ensure that families are consistently given up-to-date and balanced information about the condition, delivered in a supportive and respectful manner.

What I wish I knew then...reflections from personal experiences in counseling about Down syndrome.

Sharing the news about a newborn baby's diagnosis of Down syndrome with families is a scenario genetic counselors frequently face. Yet often we may feel uncomfortable or unsure how to best support families in this setting in a way that will foster competence and resilience. This commentary is a reflection of one genetic counselor's experiences in counseling about Down syndrome over the course of her career and how her thinking has transitioned from a medical based model of disability to a more individual and family-focused model. Ideas and suggestions are offered that genetic counselors can incorporate into their practice.