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The gastrointestinal tract
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
The underlying cause of Hirschsprung disease should be considered. It may be (1) chromosomal, in about 12% of cases, with the most frequent single condition being Down syndrome. Then (2) there are the monogenic, syndromic forms. Hirschsprung disease is a significant complication of Mowat-Wilson syndrome and FG syndrome and is also a feature of Bardet-Biedl syndrome, congenital central hypoventilation, cartilage hair hypoplasia, Goldberg-Shprintzen syndrome and Waardenburg syndrome type 4 (among others). (3) There are the monogenic non-syndromic forms, associated especially with variants of low penetrance in the RET proto-oncogene but variants in other genes can be associated (including EDN3 and EDNRB). Pathogenic variants in RET act as a Mendelian predisposition to the condition but are not sufficient to cause it. Then, finally (4) there are those cases that are non-syndromic but without a recognised molecular predisposition.
A History of Mental Retardation
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Giovanni Neri, Francesco D. Tiziano
In 1965, Reed and Reed published their famous book Mental Retardation: A Family Study (58), again missing the opportunity to provide an explanation for the excess of males in their sample of retarded subjects. However, they did make an interesting observation, namely that 9.1% of offspring of mentally retarded males and their mates with normal or unknown intelligence were mentally retarded, whereas this percentage rose to 19.4% in offspring of mentally retarded women mating with males of normal or unknown intelligence. It took almost another decade before Robert Lehrke came up with the correct interpretation of the phenomenon, attributing it to the existence of genes on the X chromosome, the mutation of which causes mental deficit, more likely to be expressed in the hemizygous males than in the heterozygous females (59). As a graduate student of John Opitz, he had access to XLMR families that were studied at the University of Wisconsin, and that also led to the definition of several specific syndromes, such as the FG syndrome (60), the Waisman–Laxova syndrome (61), the W syndrome (62), and others.
Eye and ocular adnexa manifestations of MED12-related disorders
Published in Ophthalmic Genetics, 2022
Arth Shah, Monika Bapna, Hind Al-Saif, Rachel Li, Natario L. Couser
Background:MED12-related disorders are a rare group of intellectual disability syndromes, which involve disease-causing variants in the MED12 gene located on chromosome Xq13. This gene encodes the mediator complex subunit 12. The mediator complex is a unit composed of 25 proteins, and links transcription factors with RNA polymerase II, which is involved in transcription process. The mediator complex plays a role in transcriptional activation and repression of genes involved with the Wnt signaling pathway and SHH pathway, which are known to be crucial for embryonic cell differentiation and the developmental process (1). The syndrome was initially reported in a family of five affected males with intellectual disability, macrocephaly, and hypotonia, as described by John M. Opitz & Elisabeth G. Kaveggia, and was named FG Syndrome (OMIM #305450) using the Opitz system of using initials of the patients’ surname, also called Opitz-Kaveggia syndrome (2). This syndrome, in addition to Lujan-Fryns syndrome (OMIM #309520) and Ohdo syndrome (OMIM #300895) now represent a phenotypic spectrum of MED12-related disorders (3). Common findings within this spectrum include intellectual disability and characteristic craniofacial features. FG syndrome is characterized by macrocephaly, tall forehead, abnormal corpus callosum, downslanting palpebral fissures, small ears, broad thumbs, and hypotonia (4). Lujan-Fryns syndrome is characterized by cognitive impairment, macrocephaly, abnormalities of the corpus callosum, high narrow palate, short philtrum, thin body habitus, and hypotonia (5). Ohdo syndrome is characterized by intellectual disability, facial coarsening, and blepharophimosis (6). Additionally, there have been other less common phenotypes within the phenotypic spectrum; reported clinical features among these include retinal detachment, glaucoma, cataracts, and mild intellectual disability in heterozygous females (7,8).