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Disorders of Keratinization and Other Genodermatoses
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Roselyn Stanger, Nanette Silverberg
Definition: This is a very rare autosomal dominant RASopathy characterized by lax (or redundant) skin (especially over the neck, hands, and feet), internal organ involvement (primarily cardiac), increased risk of malignancies, and severe feeding difficulties. Most patients have de novo mutations.
Non-Invasive Prenatal Testing (NIPT)
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Nuria Balaguer, Emilia Mateu-Brull, Miguel Milán
This wealth of options drove the commercial sector to update its product portfolio to offer basic panels (T13, T18, T21, and SCAs) along with more complex screening options. Genome-wide detection of fetal de novo mutations and the study of maternal inheritance are also likely to become available. The cfDNA test for single-gene disorders, termed non-invasive prenatal diagnosis (NIPD), encompasses an increasing array of conditions but is less widely available (18). Additional emerging areas of investigation include determining the relationship between circulating DNA and nucleosomal structure (19,20), the tissues of origin of circulating DNA (21,22), and whether cffDNA has any biological or pathogenic function.
Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
Family history: false negative if poorly penetrant disorder, e.g. DYT1. Think in de novo mutations in patients with unaffected parents, particularly if there is childhood onset. Interrogate for missing relatives and unusual deaths.
Current concepts on ocular vascular abnormalities in the phakomatoses
Published in Seminars in Ophthalmology, 2021
Alessandro de Paula, Solmaz Abdolrahimzadeh, Serena Fragiotta, Mariachiara Di Pippo, Gianluca Scuderi
NF 1 has a prevalence of about 1:3000 people without a relationship to gender, race, ethnic group, and geographical area.23 It is a dominant autosomal disease with complete penetrance and extremely variable expressivity,24–27 caused by mutation of the NF1 gene, which is a tumor suppressor gene, located on chromosome 17q11.2.27 In about 50% of patients the disease is due to de novo mutations.24 Affected patients can develop benign and malignant tumors. A minimum of two of the following signs are required for diagnosis according to the NIH diagnostic criteria: six or more café-au-lait spots, two or more neurofibromas or 1 or more plexiform neurofibromas, axillary or inguinal freckling, optic glioma, 2 or more iris Lisch nodules, distinctive bony lesions, and a first-degree relative with NF1.28 The major NF1 ophthalmological signs are Lisch nodules and optic pathway gliomas.12,15–17,29–31 Other ocular signs that are not in the NIH diagnostic criteria include a possible pulsating ptosis in patients where the greater wing of the sphenoid is absent, plexiform neurofibroma of the eyelid, sporadic conjunctival neurofibroma, glaucoma, and corneal nerve thickening.32,33 Recently, with the widespread use of NIR, choroidal nodules have been proposed as an additional diagnostic criterion.12–14,34,35 Choroidal alterations appear as rounded or patchy areas of hyperreflectivity on NIR images and round or placoid nodules in the choroid in cross-sectional SDOCT with enhanced depth imaging.14,36
NYX-related Congenital Stationary Night Blindness in Two Siblings due to Probable Maternal Germline Mosaicism
Published in Ophthalmic Genetics, 2021
H. l. Scanga, A. Liasis, M. S. Pihlblad, K. K. Nischal
In the described pedigree, it was concluded that maternal mosaicism involving the germline was the most likely explanation as two affected siblings have the same pathogenic variant which is absent in the mother. Mosaicism beyond the germline cannot be completely excluded in this mother as genetic testing was only performed in two sample types and female carriers of CSNB do not manifest clinical symptoms to suggest low-level somatic mosaicism. The possibility of a de novo mutation can be ruled out by the observation of the variant in two affected children and independent sample collections and genetic tests decreased the chance of human or laboratory error. Formal testing to confirm maternity was not pursued since there was no suspicion of non-biological relationships in this family, but such testing is available when relationships are questioned. Further validation of mosaicism can be obtained by haplotype analysis of informative markers surrounding a variant of interest or molecular testing of DNA from multiple tissues of similar or different embryologic lineage (11). Such investigations were not performed in this case and are limitations of this study.
A de novo mutation in PRICKLE1 associated with myoclonic epilepsy and autism spectrum disorder
Published in Journal of Neurogenetics, 2018
Brittany P. Todd, Alexander G. Bassuk
Patient x is a 7-year-old boy. He presented at 11 months with abnormal body movements consistent with myoclonic seizures. EEG demonstrated generalized epileptiform discharges. MRI was normal (Figure 1). The patient was significantly delayed in meeting his motor milestones; he sat up at 18 months, and walked at 2 ½ years. At 6 years of age, he was clinically evaluated for behavioral concerns and was diagnosed with autism spectrum disorder and a mild intellectual disability. After informed consent was obtained from an IRB approved protocol from the University of Iowa, clinical whole exome sequencing was performed on DNA isolated from Patient x and from the parents, revealing a de novo mutation in the PRICKLE1 gene c0.1444 G > A, D482N (Figure 1). No other de novo mutations were identified, nor were any other mutations in known disease-causing genes uncovered, including known global developmental delay, autism spectrum disorder, and epilepsy genes (Supplementary Table 1). Genes evaluated include those from the GeneDx epilepsy panel (https://www.genedx.com/test-catalog/available-tests/comprehensive-epilepsy-panel/). The de novo mutation was validated by Capillary sequencing. This variant was absent from over 6500 alleles in the Exome Variant Server (http://evs.gs.washington.edu/EVS/) and absent from the 60,706 individuals from the ExAc Browser (http://exac.broadinstitute.org/). Sequence alignment shows that the D482N encoding PRICKLE1 mutation alters an amino acid conserved throughout vertebrate evolution.