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Clinical Cancer Genetics
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Rosalind A. Eeles, Lisa J. Walker
Initial clinical examination involves looking for any dysmorphic features and congenital anomalies. The skin should be carefully examined, as many cancer syndromes are associated with dermatological features, such as pigmentary abnormalities, e.g. freckles on the lip in Peutz–Jeghers syndrome, café-au-lait patches in neurofibromatosis type I or Turcot’s syndrome, or basal cell naevi in Gorlin’s syndrome. Skin tumors, such as the epidermoid cysts seen in familial adenomatous polyposis (FAP), keratoacanthomas seen in Muir–Torre syndrome, or trichilemmomas of Cowden syndrome, can be indicators that the individual is very likely to be a gene carrier before confirmation by formal DNA genetic testing.
Mevalonic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Dysmorphic features were described in all but a few patients [7, 17], but were described as subtle in four [6]. The characteristic picture (Figures 85.6 and 85.7) is of dolichocephaly with frontal bossing, posteriorly rotated low-set ears, antimongoloid slanting of the eyes, a small mouth and jaw, and thin lips. One patient [1] had a small penis and a congenital hydrocele. In this boy, closure of fontanelles and sutures was delayed; by 19 months they were all widely patent. A third fontanelle may be present. Another of our patients had even more delayed closure of sutures, but she was found to have cleidocranial dysplasia and apparently independent mutations in the RUNX2 gene (Figure 85.8).
Dysmorphology and genetic syndromes
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
In case any reader should think that these scientific developments make clinical skills redundant, it should be emphasised that the reverse is the case. It is only possible to use the new laboratory approaches effectively by using an effective combination of (1) targeting appropriate panels of genes for analysis, where this is most likely to yield a diagnosis without generating too many distracting variants of uncertain significance (VUSs) and incidental findings (IFs) and (2) whole exome or whole genome approaches (array comparative genomic hybridisation [aCGH], whole exome sequencing [WES], WGS) where targeted analyses are unlikely to be fruitful. Furthermore, familiarity with the clinical features of many disorders and a careful clinical examination conducted with sensitivity will often be needed to come to a judgement as to whether a specific genetic variant is likely to have led to the particular phenotype observed. However, the contribution of the clinical geneticist to the care of patients with dysmorphic features is certainly changing as more children have molecular investigations performed before being referred for a clinical genetics assessment.
Identification of a novel nonsense variant in FYCO1 gene associated with infantile cataract and cortical atrophy
Published in Ophthalmic Genetics, 2021
Raffi Aprahamian, T. Yammine, N. Salem, M. Souaid, H. Mansour, C. Farra
Clinical examination revealed no dysmorphic features or physical abnormalities. Furthermore, no developmental delay was reported. While general physical aspect and assessment were apparently within normal range, brain MRI showed the presence of a moderate frontal bilateral cortical atrophy with enlarged aspect of the right and left frontal cortical furrows. No other detectable malformation in the corpus callosum, ventricular system, or sylvian valleys were noted. The external appearance of the eyes was normal with absence of lesions of the individualizable optic nerves and chiasma. Abdominal ultrasound as well as brain CT scan showed no malformations. Pupillary light reflexes were abnormal, showing leukocoria in both eyes. Lack of ability to stare at and follow objects adequately, except when they are very bright and present on the left lateral side of the head, was also noted. Upon inspection, lenses in both eyes showed opacity suggestive of cataract.
Foetal phenotype of ALG1-CDG caused by paternal uniparental disomy 16
Published in Journal of Obstetrics and Gynaecology, 2021
Ya-Li Lei, Li Zhen, Li-Li Xu, Yan-Dong Yang, Dong-Zhi Li
The type of CDG depends on which enzyme is involved. ALG1-CDG belongs to the five most common CDG disorders along with PMM2-CDG, ALG6-CDG, MPI-CDG and SRD5A3-CDG. Its phenotype is characterised by a predominant neurological involvement. Other dysmorphic features are reported in postnatal patients (Ng et al. 2016). Up to now, only one family of ALG1-CDG has been detected prenatally. A Dutch family experienced recurrent nonimmune hydrops fetalis in their two consecutive pregnancies, with one foetus at 32 weeks and the other at 30 weeks (Schwarz et al. 2004). Only the second patient was tested for ALG1 gene, and confirmed to have the homozygous c.773C > T variant, inherited from his heterozygous parents. The present foetus was another prenatal case with the same ALG1 variant, characterised by an increased NT and asymmetric IUGR. This provides additional information on the prenatal phenotypes of ALG1-CDG, especially for the homozygous c.773C > T variant.
Co-occurring medical conditions among individuals with ASD-associated disruptive mutations
Published in Children's Health Care, 2020
Evangeline C. Kurtz-Nelson, Jennifer S. Beighley, Caitlin M. Hudac, Jennifer Gerdts, Arianne S. Wallace, Kendra Hoekzema, Evan E. Eichler, Raphael A. Bernier
Reflecting the presence of dysmorphic features and congenital anomalies, several gene groups were uniquely characterized by physical and structural abnormalities. Macrocephaly was most strongly associated with PPP2R5D, which is consistent with the hypothesis that mutations in this gene contribute to overgrowth (Shang et al., 2016). DYRK1A was strongly associated with microcephaly, which reflects this gene’s role in neurogenesis and brain growth (Evers et al., 2017). Elevated rates of cardiac problems in ADNP and PACS1, genital problems in PACS1 and SETBP1, and vision problems in ADNP, ARID1B, and DYRK1A highlight the impact of ASD-risk genes on multiple organ systems and overall development. Exploratory analyses also indicated other gene groups that may be at risk for additional co-occurring conditions. For example, cardiac problems were reported for 42.3% of individuals with mutations in DYRK1A, and vision problems were reported for 87.5% of individuals with MED13L mutations; these rates are higher than reported in published literature reviews (Luco et al., 2016; Tørring et al., 2019). Finally, major surgical history appeared to be elevated across groups, which could reflect the presence of structural abnormalities or other medical concerns requiring intensive medical treatment.