Cécile Masson

Integrin Alpha 8 Recessive Mutations Are Responsible for Bilateral Renal Agenesis in Humans

Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease.

Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome.

Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558(∗)], c.2182C>T [p.Arg728(∗)], c.6366+3A>T [p.Gly2102Valfs5(∗)], and c.6664+5G>T [p.Ala2221Valfs23(∗)]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.

Mutations in Endothelin 1 Cause Recessive Auriculocondylar Syndrome and Dominant Isolated Question-Mark Ears

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder with mandibular hypoplasia and question-mark ears (QMEs) as major features. QMEs, consisting of a specific defect at the lobe-helix junction, can also occur as an isolated anomaly. Studies in animal models have indicated the essential role of endothelin 1 (EDN1) signaling through the endothelin receptor type A (EDNRA) in patterning the mandibular portion of the first pharyngeal arch. Mutations in the genes coding for phospholipase C, beta 4 (PLCB4) and guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 (GNAI3), predicted to function as signal transducers downstream of EDNRA, have recently been reported in ACS. By whole-exome sequencing (WES), we identified a homozygous substitution in a furin cleavage site of the EDN1 proprotein in ACS-affected siblings born to consanguineous parents. WES of two cases with vertical transmission of isolated QMEs revealed a stop mutation in EDN1 in one family and a missense substitution of a highly conserved residue in the mature EDN1 peptide in the other. Targeted sequencing of EDN1 in an ACS individual with related parents identified a fourth, homozygous mutation falling close to the site of cleavage by endothelin-converting enzyme. The different modes of inheritance suggest that the degree of residual EDN1 activity differs depending on the mutation. These findings provide further support for the hypothesis that ACS and QMEs are uniquely caused by disruption of the EDN1-EDNRA signaling pathway.

Mild B-cell lymphocytosis in patients with a CARD11 C49Y mutation

of the KU Leuven. X.B. is a senior clinical investigator of the Research Foundation Flanders. R.R. received a fellowship from the French Ministry of Research. E.M. is supported by a fellowship of the Cancer League (France). S.L. is a senior scientist from the French National Center for Scientific Research. Disclosure of potential conflict of interest: H. Schaballie has received research support from FWO Research Foundation Flanders. A. Fischer has been supported by a senior European Research Council (ERC) grant ‘‘PIDIMMUN’’ (grant no. 249816). I. Meyts has received research support from the Jeffrey Modell Foundation and has received lecture fees from Gilead Sciences. The rest of the authors declare that they have no relevant conflicts of interest.

Homozygous truncating mutation of the KBP gene, encoding a KIF1B-binding protein, in a familial case of fetal polymicrogyria

Polymicrogyria (PMG) is a clinically heterogeneous malformation of cortical development, characterized by a loss of the normal gyral pattern that is replaced by many small and infolded gyri separated by shallow sulci that are partly fused in their depths. Causes of PMG are heterogeneous and include acquired and genetic causes. There are more than 100 syndromes possibly associated with PMG but mutations in specific genes such as SRPX2, GPR56, TUBB2B, TUBB3, NHEJ1, TUBA1A, TUBA8, and WDR62 have been reported only in a minority of patients.

FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases

Hearing loss and visual impairment in childhood have mostly genetic origins, some of them being related to sensorial neuronal defects. Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family. FDXR encodes the mitochondrial ferredoxin reductase, the sole human ferredoxin reductase implicated in the biosynthesis of iron-sulfur clusters (ISCs) and in heme formation. ISC proteins are involved in enzymatic catalysis, gene expression, and DNA replication and repair. We observed deregulated iron homeostasis in FDXR mutant fibroblasts and indirect evidence of mitochondrial iron overload. Functional complementation in a yeast strain in which ARH1, the human FDXR ortholog, was deleted established the pathogenicity of these mutations. These data highlight the wide clinical heterogeneity of mitochondrial disorders related to ISC synthesis.

Recurrent KIF5C mutation leading to frontal pachygyria without microcephaly

To the editorKIF5C(NM_004522.2) mutationwas originallyreportedinafamily with congenital microcephaly and frontalpolymicrogyria.Thesepatientscarriedagermlinemosaicmu-tation (p.Glu237Val) [1]. Recently, a mutation affecting thesame residue (p.Glu237Lys) was reported in a patient withpostnatal microcephaly and frontal pachygyria [2].Pachygyria is considered to be at the less severe end of thespectrum of lissencephaly and encompasses a broader spec-trum of clinical features [3]. Pachygyria and lissencephalyhave a shared genetic basis (LIS1, DCX, TUBA1A)butpachygyria can also be observed in other conditions (ACTB,ACTG1,RELN,DYNC1H1mutations).However,themajorityof sporadic cases of pachygyria remains unexplained.

Prenatal and postnatal presentations of corpus callosum agenesis with polymicrogyria caused by EGP5 mutation

EPG5‐related Vici syndrome is a rare multisystem autosomal recessive disorder characterized by corpus callosum agenesis (ACC), hypopigmentation, cataracts, acquired microcephaly, failure to thrive, cardiomyopathy and profound developmental delay, and immunodeficiency. We report here the first case of prenatally diagnosed Vici syndrome with delayed gyration associated with ACC. Trio based exome sequencing allowed the identification of a compound heterozygous mutation in the EPG5 gene. Our patient subsequently demonstrated severe developmental delay, hypopigmentation, progressive microcephaly, and failure to thrive which led to suspicion of the diagnosis. Her MRI demonstrated ACC with frontoparietal polymicrogyria, severe hypomyelination, and pontocerebellar atrophy. This prenatal presentation of malformations of cortical development in combination with ACC expands the EPG5‐related phenotypic spectrum. Our report supports the idea that EPG5‐related Vici syndrome is both a neurodevelopmental and neurodegenerative disorder.

A novel recurrent LIS1 splice site mutation in classic lissencephaly

A Novel Recurrent LIS1 Splice Site Mutation in Classic Lissencephaly Marion Philbert, Camille Maillard, Mara Cavallin, Alice Goldenberg, Cecile Masson, Nathalie Boddaert, Adrienne El Morjani, Julie Steffann, Jamel Chelly, Xavier Gerard, and Nadia Bahi-Buisson* Imagine Institute and UMR1163, Paris Descartes—Sorbonne Paris Cit e University, Paris, France INSERM UMR-1163, Embryology and Genetics of Congenital Malformations, Paris, France Service de G en etique, CHU de Rouen et Inserm U1079, Centre Normand de G enomique M edicale et M edecine Personnalis ee, Universit e de Rouen, Rouen, France Plateforme Bioinformatique, Imagine Institute, Paris Descartes—Sorbonne Paris Cit e University, Paris, France Department of Pediatric Radiology, Hôpital Necker Enfants Malades, AP-HP, University Ren e Descartes, PRES Sorbonne Paris Cit e, Paris, France INSERM U1000 and UMR 1163, Brain Imaging Laboratory “Image at Imagine” Institut Imagine, Paris, France Genetic Department, Hôpital Necker-Enfants Malades, Paris, France Institut de G en etique et de Biologie Mol eculaire et Cellulaire, Illkirch, France Centre National de la Recherche Scientifique, Illkirch, France Institut National de la Sant e et de la Recherche M edicale, Illkirch, France Universit e de Strasbourg, Strasbourg, France Service de Diagnostic G en etique, Hôpital Civil de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg, France INSERM UMR-1163, Laboratory of Genetics in Ophthalmology, Paris, France Pediatric Neurology, Necker Enfants Malades University Hospital, AP-HP, University Ren e Descartes, PRES Sorbonne Paris Cit e, Paris, France