Novel Genetic Diagnoses in Septo-Optic Dysplasia.

Septo-optic dysplasia (SOD) is a developmental phenotype characterized by midline neuroradiological anomalies, optic nerve hypoplasia, and pituitary anomalies, with a high degree of variability and additional systemic anomalies present in some cases. While disruption of several transcription factors has been identified in SOD cohorts, most cases lack a genetic diagnosis, with multifactorial risk factors being thought to play a role. Exome sequencing in a cohort of families with a clinical diagnosis of SOD identified a genetic diagnosis in 3/6 families, de novo variants in SOX2, SHH, and ARID1A, and explored variants of uncertain significance in the remaining three. The outcome of this study suggests that investigation for a genetic etiology is warranted in individuals with SOD, particularly in the presence of additional syndromic anomalies and when born to older, multigravida mothers. The identification of causative variants in SHH and ARID1A further expands the phenotypic spectra associated with these genes and reveals novel pathways to explore in septo-optic dysplasia.

A Rare Combination of Functional Disomy Xp, Deletion Xq13.2-q28 Spanning the XIST Gene, and Duplication 3q25.33-q29 in a Female with der(X)t(X;3)(q13.2;q25.33).

We report a 19-year-old female patient with a history of short stature, primary ovarian insufficiency, sensorineural hearing loss, sacral teratoma, neurogenic bladder, and intellectual disability with underlying mosaicism for der(X)t(X;3)(q13.2;q25.33), a ring X chromosome, and monosomy X. Derivative X chromosomes from unbalanced X-autosomal translocations are preferentially silenced by the XIST gene (Xq13.2) located within the X-inactivation center. The unbalanced X-autosomal translocation in our case resulted in loss of the XIST gene thus precluding the inactivation of the derivative X chromosome. As a result, clinical features of functional disomy Xp, Turner's syndrome, and duplication 3q syndrome were observed. Importantly, indications of the derivative X chromosome were revealed by microarray analysis following an initial diagnosis of Turner's syndrome made by conventional cytogenetic studies approximately 18 months earlier. This case demonstrates the importance of utilizing microarray analysis as a first-line test in patients with clinical features beyond the scope of a well-defined genetic syndrome.

Mosaic Trisomy 9p in a Patient with Mild Dysmorphic Features and Normal Intelligence.

To the Editor: Partial and whole duplications of the short arm of chromosome 9 have been commonly reported in the literature with characteristic phenotypic features and intellectual disabilities. The clinical features of 9p duplications are broad and can include growth retardation, developmental delay, intellectual disability, microbrachycephaly, deep set eyes, hypertelorism, downslanting palpebral fissures, prominent nasal root, bulbous nasal tip, low-set ears, short fingers and toes with hypoplastic nails, and delayed bone age (Bonaglia et al., 2002; Zou et al., 2009; Guilherme et al., 2014).

Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻5). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.

Genetic counseling practice analysis.

The American Board of Genetic Counseling (ABGC) performed a genetic counseling practice analysis (PA) to determine the content of the certification examination. The ABGC-appointed PA Advisory Committee worked with psychometricians to develop a survey which was distributed to 2,038 genetic counselors in the United States and Canada. The survey was also accessible on the ABGC website. Multiple criteria were used to establish the significance of the tasks included in the survey. A total of 677 responses were used in the analysis, representing a 37.1% corrected response rate. Five major content domains with 143 tasks were identified in the PA. New certification test specifications were developed on the basis of PA results and will be used in developing future examination forms. In keeping with credentialing standards, ABGC plans to conduct a PA on a regular basis so that the content of the examination reflects current practice.