The introduction of diagnostic clinical genome and exome sequencing (CGES) is changing the scope of practice for clinical geneticists. Many large institutions are making a significant investment in infrastructure and technology, allowing clinicians to access CGES especially as health care coverage begins to extend to clinically indicated genomic sequencing-based tests. Translating and realizing the comprehensive clinical benefits of genomic medicine remains a key challenge for the current and future care of patients. With the increasing application of CGES, it is necessary for geneticists and other health care providers to understand its benefits and limitations, in order to interpret the clinical relevance of genomic variants identified in the context of health and disease. Establishing new, collaborative working relationships with specialists across diverse disciplines (e.g., clinicians, laboratorians, bioinformaticians) will undoubtedly be key attributes of the future practice of clinical genetics and may serve as an example for other specialties in medicine. These new skills and relationships will also inform the development of the future model of clinical genetics training curricula. To address the evolving role of the clinical geneticist in the rapidly changing climate of genomic medicine, two Clinical Genetics Think Tank meetings were held which brought together physicians, laboratorians, scientists, genetic counselors, trainees and patients with experience in clinical genetics, genetic diagnostics, and genetics education. This paper provides recommendations that will guide the integration of genomics into clinical practice.

Background Opitz G/BBB syndrome is a heterogeneous disorder characterised by variable expression of midline defects including cleft lip and palate, hypertelorism, laryngealtracheoesophageal anomalies, congenital heart defects, and hypospadias. The X-linked form of the condition has been associated with mutations in the MID1 gene on Xp22. The autosomal dominant form has been linked to chromosome 22q11.2, although the causative gene has yet to be elucidated. Methods and results In this study, we performed whole exome sequencing on DNA samples from a three-generation family with characteristics of Opitz G/BBB syndrome with negative MID1 sequencing. We identified a heterozygous missense mutation c.1189A>C (p.Thr397Pro) in SPECC1L, located at chromosome 22q11.23. Mutation screening of an additional 19 patients with features of autosomal dominant Opitz G/BBB syndrome identified a c.3247G>A ( p.Gly1083Ser) mutation segregating with the phenotype in another three-generation family. Conclusions Previously, SPECC1L was shown to be required for proper facial morphogenesis with disruptions identified in two patients with oblique facial clefts. Collectively, these data demonstrate that SPECC1L mutations can cause syndromic forms of facial clefting including some cases of autosomal dominant Opitz G/BBB syndrome and support the original linkage to chromosome 22q11.2.

Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders caused by defects in lysosomal function that lead to multiorgan system damage. Due to wide clinical variability within even a single disorder, making a diagnosis can be difficult and identification may be delayed. Enzyme replacement therapy (ERT) was first approved as a treatment for the LSD Gaucher disease in 1991. ERT development for other LSDs followed, and ERT is currently approved for eight LSDs in the United States. ERT may help slow progression and improve clinical symptoms, but it cannot affect neurologic features due to its inability to cross the blood-brain barrier. Additional therapies for LSDs that have been investigated include stem cell transplants, gene therapy, small molecule approaches, and genome editing. Although newer approaches seem promising, there is no "cure" for any LSDs, and management remains focused on early diagnosis and treatment. [Pediatr Ann. 2018;47(5):e191-e197.].

Trisomy 9 mosaic syndrome (T9M) is a rare condition characterized by multiorgan system involvement including craniofacial dysmorphisms, cardiac, genitourinary (GU), skeletal, and central nervous system (CNS) abnormalities. Although more than 100 cases have been reported in the literature, a comprehensive review has not been performed nor have clinical guidelines been established. Therefore, we describe the clinical features of 16 additional patients, review features of previously reported individuals, and suggest clinical guidelines. Our findings expand the clinical phenotype of T9M, including novel features of amblyopia, astigmatism, corectopia of pupil, posterior embryotoxon, and diaphragmatic eventration. Most patients had prenatal and perinatal issues, particularly from respiratory, growth, and feeding standpoints.Although small birth parameters were common, long-term growth trends varied widely. An association with advanced parental ages was also identified. The spectrum of growth and development was wide, ranging from nonverbal patients to those able to participate in educational programs with age-appropriate peers. The severity of clinical outcomes was unrelated to blood lymphocyte mosaicism levels. Microarray analysis had a higher diagnostic rate compared to standard karyotype analysis and should be utilized if this diagnosis is suspected. Future longitudinal studies will be key to monitor long-term outcomes of individuals with T9M and determine best practices for clinical management.

Preimplantation genetic testing for monogenic disorders (PGT‐M) was originally developed to identify embryos affected with serious childhood‐onset disorders, but its use has recently broadened. Guidance on the use of PGT‐M in the United States (U.S.) is currently limited, with no formal laws or guidelines established on its use. The goals of this study were to determine for which types of conditions U.S. laboratories currently do not offer PGT‐M, to explore ethical considerations U.S. laboratory genetic counselors (GCs) take into consideration when deciding to accept or reject a PGT‐M request, and to explore whether U.S. laboratory GCs believe PGT‐M should be offered for conditions with reduced penetrance or for variants of uncertain significance (VUS). Qualitative analysis of semi‐structured interviews with nine genetic counselors, from five different PGT‐M laboratories, was conducted. Participants were required to be GCs working at a PGT‐M laboratory in the U.S. and either actively counsel patients on PGT‐M or determine a patient's eligibility for PGT‐M. Two participants reported their separate laboratories have no limitations for allowable PGT‐M testing, while the other seven participants representing three other laboratories reported having limitations. The main ethical consideration GCs reported considering when deciding to accept or reject a PGT‐M request was patient autonomy, with a focus on the patient understanding risks of the testing. All participants reported believing PGT‐M should be allowable for conditions with reduced penetrance and VUS, with all participants stating their respective laboratories allow for this currently. However, all participants reported a lack of sufficient guidelines and that having guidelines from a professional organization would be beneficial to their practice. In conclusion, lack of current guidelines in the United States has created discrepancies between PGT‐M laboratories. PGT‐M laboratory GCs support the use of PGT‐M for conditions with reduced penetrance and VUS with informed consent. The need for guidelines is supported.

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