Lucile Boutaud

Delineation of EFTUD2 Haploinsufficiency-Related Phenotypes Through a Series of 36 Patients

Mandibulofacial dysostosis, Guion‐Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss‐of‐function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.

Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

Clinical, genetic and neuropathological findings in a series of 138 fetuses with a corpus callosum malformation.

BACKGROUND Corpus callosum malformation (CCM) is the most frequent brain malformation observed at birth. Because CCM is a highly heterogeneous condition, the prognosis of fetuses diagnosed prenatally remains uncertain, making prenatal counseling difficult. METHODS AND RESULTS We evaluated retrospectively a total of 138 fetuses, 117 with CCM observed on prenatal imaging examination, and 21 after postmortem autopsy. On ultrasound and/or magnetic resonance imaging, CCM was either isolated (N = 40) or associated with other neurological (N = 57) or extra cerebral findings (N = 21/20, respectively). RESULTS Most fetuses (N = 132) remained without a diagnosis at the time of pregnancy termination. This emphasizes the need to establish a neuropathological classification and to perform a genomic screening using comparative genomic hybridization. A neuropathological examination performed on 138 cases revealed a spectrum of CCMs, classified as follows: agenesis of corpus callosum (55), CC hypoplasia (30), CC dysmorphism (24), and CCM associated with a malformation of cortical development (29). Of interest, after fetopathological examination, only 16/40 malformations were classified as isolated, highlighting the importance of the autopsy following termination of pregnancy. Among the 138 cases, the underlying etiology was found in 46 cases: diabetes (one case), cytomegalovirus infection (one case), 23 chromosome abnormalities, and 21 mendelian conditions. CONCLUSION In our series of 138 cases of CCM, prenatal and postmortem examinations identified a variety of genetic causes. However, no diagnosis could be established in 67% of cases. The classification based on the underlying neurodevelopmental defects paves the way for further genetic studies and genotype-phenotype correlations.

ARID1B mutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability

Sir, In their extensive review article in Brain , Edwards et al. (2014) presented physiological processes underlying the formation of the corpus callosum, as well as pathological conditions in mice and humans leading to agenesis of the corpus callosum (AgCC). They reviewed most human syndromes associated with AgCC and emphasized the great heterogeneity of known genetic causes of AgCC in humans by listing more than 70 single gene mutations and copy number variations (CNV), which altogether explain 30–45% of all cases. Most of these genetic anomalies are responsible for AgCC associated with other cerebral or extra-cerebral malformations and/or intellectual disability (ID). The association between AgCC and intellectual disability is further highlighted by the higher prevalence of AgCC in individuals with intellectual disability (2–3%) versus in the general population (0.025–0.02%) (Paul et al. , 2007; Sotiriadis and Makrydimas, 2012). Thereby, given the extreme genetic heterogeneity of intellectual disability (Deciphering Developmental Disorders Study, 2015) and the number of genes involved in the formation of the corpus callosum in humans, it is not surprising that genetic causes of syndromes associating AgCC and intellectual disability are so numerous. However, the prevalence of each of these genetic anomalies in individuals with this association is currently unknown. To improve our knowledge on genetic causes of AgCC with intellectual disability, we collected prospectively clinical and molecular data from 177 individuals with anomalies of the corpus callosum (ACC, comprising patients with AgCC, or with short corpus callosum or with dysplastic corpus callosum), and intellectual disability (or developmental delay for young children; ACC-ID) between 2009 and 2015. A clinical diagnosis, further confirmed by targeted sequencing of the corresponding gene, when possible, was made for 15 patients. Among these patients, one had a diagnosis of Coffin-Siris syndrome (CSS) and a mutation in ARID1B , the major gene for Coffin-Siris …

Whole exome sequencing diagnoses the first fetal case of Bainbridge-Ropers syndrome presenting as pontocerebellar hypoplasia type 1

BACKGROUND Bainbridge-Ropers syndrome (BRPS) is a recently identified severe disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay, caused by de novo dominant loss of function mutation in the ASXL3 gene. CASE We report here the first case of prenatal BRPS in a fetus presenting with arthrogryposis on ultrasound and for pontocerebellar hypoplasia type 1 (PCH1) following neuropathological examination. The diagnosis was done by whole exome sequencing that identified a novel de novo ASXL3 mutation. We review 29 previous published cases. DISCUSSION The fetopathological examination allowed to extend the phenotype to central nervous system and the genetic study highlights ASXL3 as a dominant gene responsible for PCH1 phenotype. Recognizing heterozygous ASXL3 mutation as a cause of prenatal PCH1 is essential for both large scale molecular analysis in the NGS era and genetic counseling.

A neuropathological study of novel RTTN gene mutations causing a familial microcephaly with simplified gyral pattern

The RTTN gene encodes Rotatin, a large centrosomal protein involved in ciliary functions. RTTN mutations have been reported in seven families and are associated with two phenotypes: polymicrogyria associated with seizures and primary microcephaly associated with primordial dwarfism.

In utero ultrasound diagnosis of corpus callosum agenesis leading to the identification of orofaciodigital type 1 syndrome in female fetuses

OFD1 syndrome is a rare ciliopathy inherited on a dominant X‐linked mode, typically lethal in males in the first or second trimester of pregnancy. It is characterized by oral cavity and digital anomalies possibly associated with cerebral and renal signs. Its prevalence is between 1/250,000 and 1/50,000 births. It is due to heterozygous mutations of OFD1 and mutations are often de novo (75%). Familial forms show highly variable phenotypic expression. OFD1 encodes a protein involved in centriole growth, distal appendix formation, and ciliogenesis.

COL2A1 gene disruption by a balanced translocation t(12;15)(q13;q22.2) in familial Stickler syndrome.

COL2A1 Gene Disruption by a Balanced Translocation t(12;15)(q13;q22.2) in Familial Stickler Syndrome Céline Dupont,* Clarisse Baumann, Nathalie Le Du, Elise Schaefer, Fabien Guimiot, Lucile Boutaud, Yline Capri, Emmanuel Spaggiari, Azzedine Aboura, Brigitte Benzacken, and Anne-Claude Tabet AP-HP, Department of Genetic-Cytogenetic Unit, Robert Debre Hospital, Paris, France AP-HP, Department of Genetic-Clinical Genetic Unit, Robert Debre Hospital, Paris, France Cytogenetic Laboratory, Evreux, France AP-HP, Department of Developmental Biology, Robert Debre Hospital, Paris, France AP-HP, Cytogenetic Laboratory, Hopital Jean Verdier, Bondy, France University Paris 13, Paris, France

Novel mutations in the ciliopathy-associated gene CPLANE1 (C5orf42) cause OFD syndrome type VI rather than Joubert syndrome

Mutations in CPLANE1 (previously known as C5orf42) cause Oral-Facial-Digital Syndrome type VI (OFD6) as well as milder Joubert syndrome (JS) phenotypes. Seven new cases from five unrelated families diagnosed with pure OFD6 were systematically examined. Based on the clinical manifestations of these patients and those described in the literature, we revised the diagnostic features of OFD6 and include the seven most common characteristics: 1) molar tooth sign, 2) tongue hamartoma and/or lobulated tongue, 3) additional frenula, 4) mesoaxial polydactyly of hands, 5) preaxial polydactyly of feet, 6) syndactyly and/or bifid toe, and 7) hypothalamic hamartoma. By whole or targeted exome sequencing, we identified seven novel germline recessive mutations in CPLANE1, including missense, nonsense, frameshift and canonical splice site variants, all causing OFD6 in these patients. Since CPLANE1 is also mutated in JS patients, we examined whether a genotype-phenotype correlation could be established. We gathered and compared 46 biallelic CPLANE1 mutations reported in 32 JS and 26 OFD6 patients. Since no clear correlation between paired genotypes and clinical outcomes could be determined, we concluded that patients genetic background and gene modifiers may modify the penetrance and expressivity of CPLANE1 causal alleles. To conclude, our study provides a comprehensive view of the phenotypic range, the genetic basis and genotype-phenotype association in OFD6 and JS. The updated phenotype scoring system together with the identification of new CPLANE1 mutations will help clinicians and geneticists reach a more accurate diagnosis for JS-related disorders.

Loss of function IFT27 variants associated with an unclassified lethal fetal ciliopathy with renal agenesis

Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult‐onset disorders. Pathogenic variants in more than 100 ciliary protein‐encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT‐A) and anterograde transport (IFT‐B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c.118_125del, p.(Thr40Glyfs*11) and a c.352 +1G > T in IFT27, which encodes a small GTPase component of the IFT‐B complex. We conclude that bilateral renal agenesis is a rare feature of this severe ciliopathy and this report highlights the phenotypic overlap of Pallister–Hall syndrome and ciliopathies. The phenotype in patients with IFT27 gene variants is wide ranging from Bardet–Biedl syndrome to a lethal phenotype.