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Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF, SLC16A2, and the long non-coding RNA gene FTX. The contribution of the RLIM-flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.

Conflict resolution in genomic variant interpretation is a critical step towards improving patient care. Evaluating interpretation discrepancies in copy number variants (CNVs) typically involves assessing overlapping genomic content with focus on genes/regions that may be subject to dosage sensitivity (haploinsufficiency (HI) and/or triplosensitivity (TS)). CNVs containing dosage sensitive genes/regions are generally interpreted as “likely pathogenic” (LP) or “pathogenic” (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation. We compared the Clinical Genome Resource (ClinGen) Dosage Map, a publicly available resource documenting known HI and TS genes/regions, against germline, clinical CNV interpretations within the ClinVar database. We identified 251 CNVs overlapping known dosage sensitive genes/regions but not classified as LP or P; these were sent back to their original submitting laboratories for re-evaluation. Of 246 CNVs re-evaluated, an updated clinical classification was warranted in 157 cases (63.8%); no change was made to the current classification in 79 cases (32.1%); and 10 cases (4.1%) resulted in other types of updates to ClinVar records. This effort will add curated interpretation data into the public domain and allow laboratories to focus attention on more complex discrepancies.

Background Steroid sulfatase ( STS ) gene disruption causes X-linked ichthyosis (XLI). Interrogating the entire genome through chromosomal microarray (CMA), a test primarily used to screen patients with noncutaneous congenital anomalies, may detect STS deletions incidentally. Objective We sought to determine the variability of skin features associated with STS deletions diagnosed through CMA and to compare these findings with XLI cases reported in the literature and recognized in a dermatology clinic. Methods Male patients with an STS deletion were identified from 23,172 consecutive postnatal blood samples tested with CMA at Mayo Clinic. A comparison group of male patients with biochemically confirmed XLI was ascertained in the dermatology clinic. The available patient medical records, skin histopathology, and photographs were evaluated and a literature search of patients with XLI was conducted. Results Children whose diagnosis was made incidentally through CMA had milder skin phenotypes, including dryness or eczema, or both, and did not manifest the polygonal or "dirty" scale described as typical of XLI in the literature. Limitations The small sample size, limited clinical information, and assessment by nondermatologists in a subset of cases may have influenced the results. Conclusion STS deletions may cause a milder skin phenotype than the typical presentation of XLI.

Currarino syndrome (OMIM 175450) presents with sacral, anorectal, and intraspinal anomalies and presacral meningocele or teratoma. Autosomal dominant loss-of-function mutations in the MNX1 gene cause nearly all familial and 30% of sporadic cases. Less frequently, a complex phenotype of Currarino syndrome can be caused by microdeletions of 7q containing MNX1. Here, we report one familial and three sporadic cases of Currarino syndrome. To determine the most efficient genetic testing approach for these patients, we have compared results from MNX1 sequencing, chromosomal microarray, and performed a literature search with analysis of genotype-phenotype correlation. Based on the relationship between the type of mutation (intragenic MNX1 mutations vs 7q microdeletion) and the presence of intellectual disability, growth retardation, facial dysmorphism, and associated malformations, we propose a testing algorithm. Patients with the classic Currarino triad of malformations but normal growth, intellect, and facial appearance should have MNX1 sequencing first, and only in the event of a normal result should the clinician proceed with chromosomal microarray testing. In contrast, if growth delay and/or facial dysmorphy and/or intellectual disability are present, chromosomal microarray should be the first method of choice for genetic testing.

Aims: In September, 2015, Mayo Clinic convened a panel of national thought leaders on prenatal screening, medical genetics, and obstetrics and gynecology practice. Results: During the 2-day symposium, participants discussed the implications of the shift toward broader prenatal screening using cell-free placental DNA in maternal serum (cfDNA screening). Key topics included challenges around the pace of change in the prenatal screening market, uncertainty around reimbursement, meeting the need for patient counseling, and potential challenges in interpreting and returning cfDNA screening results. Innovation: Here, we describe the challenges discussed and offer clinical recommendations for practices who are working to meet them. Conclusion: As the spread of prenatal genetic screening continues, providers will increasingly need to update their practice to accommodate new screening modalities.

The field of genetics continues to evolve at a rapid pace. The completion of the Human Genome project coupled with advancing scientific techniques has led to the explosion of genetic information and testing capabilities ranging from rare genetic conditions to common and sometimes preventable conditions. The Online Mendelian Inheritance in Man® (OMIM) found at http://www.ncbi.nlm.nih.gov/omim contains information on over 12,000 genes with known sequence. Another online resource, GeneTests, found at http://www.ncbi.nlm.nih.gov/sites/GeneTests provides reference for nearly 1,500 diseases in which clinical laboratory testing is available. This chapter reviews a variety of genetic conditions categorized by primary mode of inheritance (i.e., chromosomal, single gene, and mitochondrial disorders) and is further subcategorized by disease process (i.e., metabolic, familial cancer syndromes, hematologic disorders). For each disorder, the chromosome, gene location, inheritance pattern, incidence, clinical phenotype, laboratory findings, and treatment options are reviewed. The chapter does not encompass all known genetic conditions, but provides a general overview of a wide range of genetic conditions and various inheritance patterns extending across multiple subspecialties. The suggested reading section provides key text books and peer reviewed references for those desiring more in-depth information.

Laboratory genetic counseling is becoming increasingly common as a result of increased laboratory services and genetic testing menus, as well as growing job responsibilities. Christian et al. (2012) provided the first quantitative data regarding the roles of the laboratory-based genetic counselor (LBGC) finding that two of the most prevalent roles are as customer liaisons and communicators of test results. The goal of the present study was to further delineate the role of the LBGC by addressing specific tasks that LBGCs are involved with on a day-to-day basis. A survey was designed to expand upon themes identified in the Christian et al. (2012) study by querying specific tasks performed in several categories of potential LBGC job duties. An invitation for LBGCs to participate was distributed via email to the membership of the National Society of Genetic Counselors (NSGC) and the Canadian Association of Genetic Counsellors (CAGC). We identified 121 genetic counselors who primarily work in the laboratory setting or whose job role includes a laboratory component. Almost all respondents performed customer liaison/case coordination (95 %), and interpretation and result reporting (88 %). The most frequently performed tasks within these categories involved addressing questions from clients, making phone calls with genetic testing results, obtaining clinical or family history information for results interpretation, and composing case-specific interpretations for unique results and/or obtaining literature references to support interpretations. The study results also point to trends of expanding roles in sales and marketing, variant interpretation and management responsibilities. Results of this study may be useful to further define the full scope of practice of LBGCs, aid in the development of new LBGC positions and expand current positions to include roles related to test development, research, and student supervision. It may also aid in curriculum updates for training programs to increase exposure to LBGC roles.

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

Chromosomal microarray (CMA) is widely used to detect and refine chromosome abnormalities in both congenital and neoplastic cases. Recently, a blood sample from a newborn male with no apparent dysmorphic features was sent to the Mayo Clinic Cytogenetics laboratory for G-banded karyotype analysis to clarify prenatal findings of a positive trisomy 21 noninvasive prenatal screening (NIPS) result. Chromosome analysis of 20 metaphases revealed 13 were normal (46,XY) and 7 had a satellited supernumerary marker chromosome (47,XY,+mar). To further characterize the marker chromosome, CMA studies were performed, which revealed an 8.6 megabase mosaic duplication from 21q11.2 to 21q21.1. Subsequent metaphase FISH studies demonstrated that the duplicated region was present on the supernumerary marker chromosome, indicating that the marker chromosome is derived from chromosome 21. Interphase FISH studies showed that the marker was present in 68% of interphase nuclei. Despite its large size, the duplicated region contains only 30 known genes. In addition, similar duplications involving this region have not been previously described, making the clinical significance of this duplication uncertain. Importantly, the duplicated interval does not include the Down syndrome critical region (21q22.1 to 22q22.3), consistent with this patient’s lack of dysmorphic features. This report highlights the importance of diagnostic follow-up testing and the clinical utility of conventional and molecular cytogenetic techniques in the setting of abnormal NIPS results.