Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis

Abstract

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Results 68 different mutations were detected in 73 patients. In patients with three or more clinical characteristics of L1 syndrome, the mutation detection rate was 66% compared with 16% in patients with fewer characteristics. The detection rate was 51% in families with more than one affected relative, and 18% in families with one affected male. A combination of these two factors resulted in an 85% detection rate (OR 10.4, 95% CI 3.6 to 30.1). The type of mutation affects the severity of L1 syndrome. Children with a truncating mutation were more likely to die before the age of 3 than those with a missense mutation (52% vs 8%; p¼0.02).Conclusions We developed a comprehensive mutation detection system with a detection rate of almost 20% in unselected patients and up to 85% in a selected group. Using the patients' clinical characteristics and family history, clinicians can accurately predict the chance of finding a mutation. A genotype-phenotype correlation was confirmed. The occurrence of (maternal) germline mosaicism was proven.

Three cases with L1 syndrome and two novel mutations in the L1CAM gene

“…In this case, we cannot rule out the possibility of parental germ cell mosaicism. At least two cases of mosaicism in L1 syndrome have been reported in the literature [9,10]. In our cases, adducted thumbs were an important clinical clue to the diagnosis.…”

“…In cases 1 and 2, family histories were consistent with X-linked intellectual disability, but the disease can appear in a child without mental retardation, as in case 3. About 7 % of L1 syndromes are due to de novo mutations [10]. In this case, we cannot rule out the possibility of parental germ cell mosaicism.…”

“…Several authors have described a correlation between the type of mutation and the severity of the syndrome [3,10,12]. Nonsense or frameshift mutations that produce a premature stop codon leading to truncation in extracellular domains or abolishing expression of the protein produce the most severe form of the syndrome, usually with severe congenital hydrocephalus and early mortality.…”

Pathologic Examination of Fetal and Placental Tissue Obtained by Dilation and Evacuation

“…The finding of adducted thumbs associated with hydrocephalus is suggestive of X-linked hydrocephalus and related syndromes. [55][56][57] Based on these pathologic findings from the D&E specimen, targeted genetic testing of the L1CAM gene was performed, and the fetus showed a deletion of the L1CAM gene. The mother was subsequently identified as a carrier.…”

Disturbed Wnt Signalling due to a Mutation in CCDC88C Causes an Autosomal Recessive Non-Syndromic Hydrocephalus with Medial Diverticulum

“…Important syndromal forms of congenital hydrocephalus include the autosomal recessive syndromal lissencephalies type 2 Walker-Warburg syndrome and Muscle-eye-brain disease with additional observation of a hypoplastic cerebellum and brainstem together with cobblestone lissencephaly and agenesis or hypoplasia of the corpus callosum as well as postnatal congenital muscular hypotonia, various eye abnormalities and global developmental delay, which in about half of the cases result from mutations in one of currently 6 genes associated with the O-glycosylation of ␣-dystroglycan [Bouchet et al, 2007]. The most frequent monogenic form of congenital hydrocephalus is due to hemizygous mutations in the L1CAM gene (about 7-15%) and clinically characterised by the distinct combination of a hydrocephalus due to stenosis of the aqueduct of Sylvius commonly in association with adducted thumbs (HSAS) [Tapanes-Castillo et al, 2010;Vos et al, 2010].…”