A Novel Mutation in PITX2 in a Patient with Axenfeld-Rieger Syndrome.

Axenfeld-Rieger syndrome is a rare autosomal dominant condition. Anomalies include anterior segment dysgenesis of the eye, dental anomalies, maxillary hypoplasia, periumbilical anomalies, and congenital heart defects. We report a patient with Peters anomaly, dysmorphic features, congenital heart defect, umbilical hernia, short stature, and developmental delay. Diagnostic sequencing of 23 genes known to be causally related to the condition was performed on the patient, parents, and maternal grandparents. A variant of uncertain significance in PITX2 was identified. The mother had the same mutation and the father did not. The mother had decreased vision, congenitally missing teeth, and required jaw surgery as a child. Her asymptomatic parents elected to be tested and were negative for the mutation. The mutation, NM_153427.2:c.272G>A (p.Arg91Gln), is predicted to be damaging by PolyPhen-2 (score of 0.997), identified as a missense mutation with an allele frequency of 1.648e-05 by the Exome Aggregation Consortium, and has been reported in ClinVar once, by the laboratory that analyzed our patient's sample. Due to the in silico predictions and the results of family studies, it is suggested that this variant can be classified as pathogenic according to the American College of Medical Genetics and Genomics 2015 rule Pathogenic(iii)(b), specifically rules PS2, PM2, PM5, PP1, and PP3.

RBPJ mutations identified in two families affected by Adams-Oliver syndrome.

Through exome resequencing, we identified two unique mutations in recombination signal binding protein for immunoglobulin kappa J (RBPJ) in two independent families affected by Adams-Oliver syndrome (AOS), a rare multiple-malformation disorder consisting primarily of aplasia cutis congenita of the vertex scalp and transverse terminal limb defects. These identified mutations link RBPJ, the primary transcriptional regulator for the Notch pathway, with AOS, a human genetic disorder. Functional assays confirmed impaired DNA binding of mutated RBPJ, placing it among other notch-pathway proteins altered in human genetic syndromes.

Chromosome 2q terminal deletion: report of 6 new patients and review of phenotype-breakpoint correlations in 66 individuals.

We report a new patient with terminal deletion of chromosome 2 with breakpoint at 2q36 and five additional new patients with 2q terminal deletion with breakpoint at 2q37. Hemidiaphragmatic hernia is a novel finding in one patient with a breakpoint at 2q37.1. In comparing these patients to 60 previously reported individuals with 2q terminal deletions, certain physical abnormalities are loosely associated with positions of breakpoint. For example, facial features (e.g., prominent forehead, depressed nasal bridge, and dysmorphic ears and nose), short stature, and short hands and feet were frequent in patients with breakpoints at or proximal to 2q37.3. Reports of horseshoe kidney and Wilms tumor were limited to patients with a breakpoint at 2q37.1, and structural brain anomalies and tracheal anomalies were reported only in patients with breakpoints at or proximal to 2q37.1. Cleft palate was reported only in patients with the most proximal breakpoints (2q36 or 2q35). Neurological effects including developmental delay, mental retardation, autistic-like behavior, and hypotonia were typical in this patient population but did not stratify in severity according to breakpoint. Terminal deletion of the long arm of chromosome 2 should be considered in the infant with marked hypotonia, poor feeding, gastroesophageal reflux, and growth delay, and the older child with developmental delay, autistic behavior, and the characteristic facial and integumentary features described herein. Assignment of clinical features to specific breakpoints and refinement of predictive value may be useful in counseling.

Genetic counseling.

Medical professionals and the public are rapidly becoming aware of the overwhelming influence that an individual's genetic constitution has on fetal health and mortality, congenital malformations, cancer and other chronic diseases. Great strides have been made in recognizing and understanding modes of inheritance that had not previously been well described. Besides single-gene disorders, genetic conditions are known to be caused by a variety of different mechanisms: chromosome microdeletions and fragility, multifactorial inheritance, mitochondrial genes, triplet repeat expansions, imprinting, and uniparental disomy. Because of the complexity of genetic information, an extensive discussion is often necessary to sort out advertising, news information, and personal health concerns to enable individuals to make decisions for themselves about the various options available for testing and treatment. Genetic counseling has developed as a discipline in response to the need to educate patients, families and professionals about genetic mechanisms and their application in health care. In the future, we anticipate that the emphasis will be on primary care physicians as health-care managers, and genetic counselors will be required to educate individuals about their personal risks of inherited disorders and the implications for future generations. Genetic counseling is a process of medical education based upon empathy, patient autonomy and confidentiality in an atmosphere of empathy, support and understanding. This profession combines the knowledge of complex medical and genetic theory with the skills of a concerned, supportive counselor.