Biallelic mutations in RTTN are associated with microcephaly, short stature and a wide range of brain malformations

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Abstract

Biallelic mutations in the RTTN gene have been reported in association with microcephaly, short stature, developmental delay and malformations of cortical development. RTTN mutations have previously shown to link aberrant ciliary function with abnormal development and organization of the human cerebral cortex. We here report three individuals from two unrelated families with novel mutations in the RTTN gene. The phenotype consisted of microcephaly, short stature, pachygyria or polymicrogyria, colpocephaly, hypoplasia of the corpus callosum and superior vermis. These findings provide further confirmation of the phenotype related to pathogenic variants in RTTN.

Introduction

Malformations of the cortical development (MCD) are a heterogeneous group of disorders, which can be caused by genetic or environmental factors, or potentially a combination of both. Over 100 genes linked to various pathways including centrosomal positioning, microtubule-dependent transport and stabilization, nuclear transport, and neuroependymal and pial membrane integrity have been shown to be essential for the normal development of the cerebral cortex (Barkovich et al., 2012; Guerrini and Dobyns, 2014).

One of the genes involved in the development of MCD is RTTN (rotatin; OMIM 610436), of which variants have first been described in a mouse model by Faisst et al. (2002). In this Rttn−/- model, the gene has been linked to axial rotation, which is crucial for the appropriate development of the mouse embryo. Furthermore, Rttn knock-out mice also showed notochord degeneration, neural tube defects, hydrocephalus, randomized heart looping and alteration of the left-right regulatory cascade symptoms often encountered in ciliopathies. The analogous gene of RTTN in Drosophila melanogaster (Ana3) is localized at the centrioles and basal body of the primary cilium. Furthermore, Ana3 deficient neuroblasts revealed its role in centriole structure, cohesion and appropriate mitotic spindle formation (Stevens et al., 2009). Recently, this role in centriole structure was confirmed for the human rotatin (Chen et al., 2017).

Kheradmand Kia et al. (2012) reported recessive RTTN mutations in two families, suffering from polymicrogyria, as a link between primary cilia function and cortical development. In this first human study describing two families with a total of five affected individuals, mutations in RTTN were associated with a thickened and irregular cortex described as polymicrogyria, most pronounced over the perisylvian area with or without extension to the parieto-occipital regions. One of the patients had bilateral temporal arachnoid cysts (Kheradmand Kia et al., 2012). The authors noted that the primary cilia in patients' and siRTTN treated fibroblasts were shorter compared to control fibroblasts. Subsequent experiments also showed downregulation of multiple genes (SHH, WNT2B, WNT5A and BMP4) known to be involved in neuronal migration, cilia regulatory pathways and which are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius neurons (Kheradmand Kia et al., 2012). Interestingly, mouse embryos show rotatin colocalization with Cajal-Retzius neurons at the subpial marginal zone. In a second paper describing three additional families, the phenotype was extended by illustrating that variants in RTTN can also be associated with a more complex brain malformation consisting of microcephaly with severe cerebral and cerebellar hypoplasia, diffuse pachygyria, incomplete separation of the cerebral hemispheres, agenesis of the corpus callosum, multiple subependymal grey-matter heterotopia and large posterior cysts. In the most severely affected patient, the majority of the supratentorial compartment was filled with cerebrospinal fluid (Shamseldin et al., 2015). The authors also highlighted the association of RTTN mutations with short stature. Finally, Grandone et al. (2016) reported two additional siblings with RTTN mutations and pachygyria, grey matter heterotopia, brain stem hypoplasia and a quadrigeminal cistern arachnoid cyst who also had congenital dermatitis as part of the phenotype. In this study, the majority of the reported patients presented with a microcephaly and short stature.

Here, we report three patients - two sisters and one unrelated girl - with three novel mutations in the RTTN gene, detected through exome sequencing, and confirmed by gene panel and Sanger sequencing. All three patients showed a spectrum of cortical malformations in combination with a short stature.

Section snippets

Patients

The first family, consisting of two siblings, born from healthy and unrelated Belgian parents, were followed for microcephaly, short stature and severe developmental delay. They have one healthy brother (Fig. 1).

The oldest sister (patient 1) was born at 40 weeks gestation. Pregnancy was complicated by a herpes zoster infection in the mother at 6 months gestation and by intra-uterine growth retardation. She was small for gestational age with a birth weight of 2.670 kg (−1.3SD). Height was 45 cm

Results

All three girls had pronounced microcephaly, short stature and severe developmental delay with absent expressive language. Brain MRI showed pachygyria or polymicrogyria, and mild colpocephaly. The corpus callosum was thin and hypoplastic. Brainstem and cerebellum were normal except for mild hypoplasia of the superior cerebellar vermis. None of the patients had periventricular grey matter heterotopia.

Trio exome sequencing was performed for patient 1. An autosomal recessive inheritance pattern

Discussion

Currently, a total of 15 patients (10 male) from eight families with disease causing variants in the RTTN gene have been described. Most had severe microcephaly, structural brain abnormalities, short stature and severe developmental delay (Kheradmand Kia et al., 2012; Shamseldin et al., 2015; Grandone et al. 2016, this report). For those patients for whom information was available, head circumference at birth varied from −3.2 SD to −5.5 SD, changing to up to −11 SD in childhood. Only one

Acknowledgements

AJ was funded by a Senior Clinical Investigator Fellowship of the Research Foundation Flanders, the Scientific Fund Willy Gepts and the VUB Research Foundation. LV was funded by a fellowship of the Foundation Marguerite-Marie Delacroix and a travel grant from the Research Foundation Flanders. SM was supported by the Foundation Marguerite-Marie Delacroix . AD was supported by a Research Fellowship from EPNS.

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