Morphological and genetic causes of fetal cardiomyopathies.

Cardiomyopathies are diseases of the heart muscle with variable clinical expressivity. Most of forms are inherited as dominant trait, and with incomplete penetrance until adulthood. Severe forms of cardiomyopathies were observed during the antenatal period with a pejorative issue leading to fetal death or medical interruption of pregnancy. Variable phenotypes and genetic heterogeneity make etiologic diagnosis difficult. We report 11 families (16 cases) whose unborn, newborn or infant with early onset cardiomyopathies. Detailed morphological and histological examinations of hearts were implemented, as well as genetic analysis on a cardiac targeted NGS panel. This strategy allowed the identification of the genetic cause of the cardiomyopathy in 8/11 families. Compound heterozygous mutations in dominant adulthood cardiomyopathy genes were found in two, pathogenic variants in co-dominant genes in one, de novo mutations in 5 including a germline mosaicism in one family. Parental testing was systematically performed to detect mutation carriers, and to manage cardiological surveillance and propose a genetic counseling. This study highlights the great diagnostic value of the genetic testing of severe antenatal cardiomyopathy both for genetic counseling and to detect presymptomatic parents at higher risk of developing cardiomyopathy.

Extending the prenatal Noonan's phenotype by review of ultrasound and autopsy data.

OBJECTIVES: The antenatal phenotypic spectrum of Noonan Syndrome (NS) requires better characterization. METHODS: This multicenter retrospective observational included 16 fetuses with molecularly confirmed NS admitted for fetopathological examination between 2009 and 2016. RESULTS: Among 12 pathogenic variants (PV) in PTPN11 (80%), 5 (42%) fell between position c.179 and c.182. Ultrasound showed increased nuchal translucency (n = 13/16, 93%), increased nuchal fold after 15 weeks of gestation (n = 12/16, 75%), pleural effusions (n = 11/16, 69%), polyhydramnios (n = 9/16, 56%), hydrops (n = 7/16, 44%), cardiovascular (n = 6/16, 38%) and cerebral (n = 4/16, 25%) anomalies. Fetopathological examination found dysmorphic features in all cases, cardiovascular anomalies (n = 12/15, 80%), pulmonary hypoplasia (n = 10/15, 67%), effusions (n = 7/15, 47%) and neuropathological anomalies (n = 5/15, 33%). Hydrops was significantly (p = 0.02) more frequent in the four fetuses with RIT1, NRAS and RAF1 PV versus the 12 fetuses with PTPN11 PV. CONCLUSIONS: Increased nuchal translucency and nuchal fold is common in NS. Noonan Syndrome antenatal phenotype showed high in utero fetal death, hydrops, prenatal pleural effusion and pulmonary hypoplasia, although the inclusion of only deceased fetuses will have selected more severe phenotypes. Non-specific cardiovascular and neurological abnormalities should be added to NS antenatal phenotype. Next generation sequencing will help detect more genotypes, clarifying the prenatal phenotype and identifying genotype-phenotype correlations.

COL4A1/COL4A2 and inherited platelet disorder gene variants in fetuses showing intracranial hemorrhage.

BACKGROUND: Variants of COL4A1/COL4A2 genes have been reported in fetal intracranial hemorrhage (ICH) cases but their prevalence and characteristics have not been established in a large series of fetuses. Fetal neonatal alloimmune thrombocytopenia is a major acquired ICH factor but the prevalence and characteristics of inherited platelet disorder (IPD) gene variants leading to thrombocytopenia are unknown. Herein, we screened COL4A1/COL4A2 and IPD genes in a large series of ICH fetuses. METHODS: A cohort of 194 consecutive ICH fetuses were first screened for COL4A1/COL4A2 variants. We manually curated a list of 64 genes involved in IPD and investigated them in COL4A1/COL4A2 negative fetuses, using exome sequencing data from 101 of these fetuses. RESULT: Pathogenic variants of COL4A1/COL4A2 genes were identified in 36 fetuses (19%). They occurred de novo in 70% of the 32 fetuses for whom parental DNA was available. Pathogenic variants in two megakaryopoiesis genes (MPL and MECOM genes) were identified in two families with recurrent and severe fetal ICH, with variable extraneurological pathological features. CONCLUSION: Our study emphasizes the genetic heterogeneity of fetal ICH and the need to screen both COL4A1/COL4A2 and IPD genes in the etiological investigation of fetal ICH to allow proper genetic counseling.

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita.

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families. METHODS: Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants. RESULTS: We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%). CONCLUSION: New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

Occupational Exposure to Ultrafine Particles and Placental Histopathological Lesions: A Retrospective Study about 130 Cases.

Ultrafine particles (UFPs) are particles smaller than 100 nanometers that are produced unintentionally during human activities or natural phenomena. They have a higher biological reactivity than bigger particles and can reach the placenta after maternal exposure. One study has shown an association between maternal occupational exposure to UFPs and fetal growth restriction. Yet few studies have focused on the effects of UFP exposure on placental histopathological lesions. The aim of this study was to investigate the association between maternal occupational exposure to UFPs and histopathological lesions of their placenta. The analyses were based on data from the ARTEMIS Center. A job-exposure matrix was used to assess occupational exposure to UFPs. The histopathological placental exam was performed by two pathologists who were blinded to the exposure of each subject. The examination was conducted in accordance with the recommendations of the Amsterdam consensus. The study sample included 130 placentas (30 exposed, 100 unexposed). Maternal occupational exposure to UFPs during pregnancy is significantly associated with placental hypoplasia (the phenomenon affected 61% of the exposed patients and 34% of the unexposed ones, p < 0.01). Further research is needed to explain its pathophysiological mechanisms.

An Atypical Case of Congenital Erythropoietic Porphyria.

Congenital erythropoietic porphyria (CEP, OMIM #606938) is a severe autosomal recessive inborn error of heme biosynthesis. This rare panethnic disease is due to a deficiency of uroporphyrinogen III synthase (or cosynthase). Subsequently, its substrate, the hydroxymethylbilane is subsequently converted into uroporphyrinogen I in a non-enzymatic manner. Of note, uroporphyrinogen I cannot be metabolized into heme and its accumulation in red blood cells results in intramedullary and intravascular hemolysis. The related clinical symptoms occur most frequently during antenatal or neonatal periods but may also appear in late adulthood. The main antenatal clinical presentation is a non-immune hydrops fetalis. We report here two cases of antenatal CEP deficiency and a review of the reported cases in the literature.

Chronic Intervillositis of Unknown Etiology: Development of a Grading and Scoring System That Is Strongly Associated With Poor Perinatal Outcomes.

Chronic intervillositis of unknown etiology (CIUE) is a rare placental disease characterized by intervillous infiltration of maternal macrophages and associated with poor pregnancy outcomes and a high risk of recurrence in subsequent pregnancies. Its pathophysiology remains unclear and prognostic factors have not yet been established. In addition, clear relationships between the histologic extent of lesions and the severity of perinatal outcomes have not been demonstrated. Our objectives were to validate a CIUE classification system based on the gradation of macrophagic infiltration of the intervillous space, and to attempt to correlate these results with perinatal outcomes. For this multicenter retrospective study, 3 pathologists reviewed all cases diagnosed with "intervillositis" between 1997 and 2018. Confirmed CIUE cases were semiquantitatively graded based on the percentage of macrophagic infiltrate in the intervillous space: grade 1 (5% to 10%), grade 2 (10% to 50%), and grade 3 (>50%). Multiple pregnancies and pregnancies with medical follow-up completed outside of the study centers were excluded. In total, 122 cases of CIUE in 102 patients were included in the study. Microscopic classification based on one criterion was easy to perform, and interobserver correlation was good. Grade 3 infiltration was strongly associated with poor perinatal outcomes and fetal growth restriction (P<0.0001). After delivery, only 16.1% of newborns from the grade 3 CIUE group were alive, compared with 59% from the grade 2 and 86.5% from the grade 1 group (P=0.0002). Recurrence risk was associated with CIUE gradation of the index case (P=0.004), with 95% of recurrent CIUE cases being from patients with grades 2 and 3 CIUE. In this study, conducted with the largest CIUE cohort to date, a classification based only on the degree of macrophagic infiltration of the intervillous space was validated, and this classification was shown to be strongly associated with poor perinatal outcomes and risk of recurrence.

Adverse perinatal outcomes of chronic intervillositis of unknown etiology: an observational retrospective study of 122 cases.

Our study aimed to assess perinatal outcomes and recurrence rate of Chronic Intervillositis of Unknown Etiology (CIUE). We conducted an observational retrospective study in a tertiary care university hospital in France from January 1, 1997 to July 31, 2018. 122 pregnancies (102 women) with CIUE were included. Cases of the Department of Histopathology placenta database were re-analysed independently by three pathologists specializing in fetal pathology. Diagnosis of CIUE was confirmed according to: (1) the presence of cellular infiltrate in the intervillous space, (2) ~ 80% of the mononuclear cells in the intervillous space positive for CD68, (3) infiltration occupying at least 5% of the intervillous space, and (4) no clinical or histopathological sign of infection. Outcomes of pregnancies with CIUE (miscarriages, stillbirths, terminations of pregnancy, live birth with or without prematurity or fetal growth restriction) and proportion of CIUE recurrence were analysed. The lost pregnancies comprised 17 (13.9%) miscarriages, 17 (13.9%) stillbirths, and 18 (14.8%) terminations of pregnancy. Of the 70 (57.4%) pregnancies that led to a live birth, 38 (54.3%) new-borns were premature and 50 (72.5%) exhibited fetal growth restriction. Among the 102 women, 23 subsequently became pregnant, half of whom (n = 11) developed recurrent CIUE. CIUE was associated with high rates of adverse perinatal outcomes, including pregnancy loss, fetal growth restriction, and preterm birth with a risk of recurrence nearly 50%.

p57-discordant villi in hydropic products of conception: a clinicopathological study of 70 cases.

p57 immunostaining is performed on hydropic products of conception to diagnose hydatidiform moles (HMs), which can progress to gestational trophoblastic neoplasia. Partial hydatidiform mole (PHM) and hydropic abortion (HA) display positive staining in stromal and cytotrophoblastic cells, whereas complete hydatidiform mole (CHM) is characterized by loss of p57 expression in both cell types. In some cases, an aberrant pattern is observed, called discordant p57 expression, with positive cytotrophoblast staining and negative stromal staining, or vice versa. The aim of this study was to describe the clinical, biological, and pathological characteristics of p57-discordant villi (p57DV) and other associated populations in cases of divergent p57 expression and to compare the evolutions of p57DV-associated and classic CHMs. Seventy cases of p57DV diagnosed by referent pathologists were divided into two groups, G1: p57DV ± non-CHM component (n = 22) and G2: p57DV + CHM component (n = 48). p57DV morphology was similar in the two groups. Observation of more than two populations and hybrid villi on p57 immunostaining were significantly more frequent in G2. The clinical, ultrasound, and biological presentations of p57DV-associated and classic CHMs were similar. The initial pathological diagnosis was more frequently incorrect, missing the CHM component, for the p57DV-associated CHMs. Molecular genotyping was informative in seven cases and identified as androgenetic/biparental mosaicism in four cases. These results show that p57DV are a diagnostic challenge for pathologists and that most are associated with a CHM component. However, the clinical management of p57DV-associated CHMs should be the same as that of classic CHMs.

Foetal onset of EIF2B related disorder in two siblings: cerebellar hypoplasia with absent Bergmann glia and severe hypomyelination.

Bi-allelic pathogenic variants in genes of the EIF2B family are responsible for Childhood Ataxia with Central nervous system Hypomyelination/Vanishing White Matter disease, a progressive neurodegenerative disorder of the central white matter. Only seven molecularly proven cases with antenatal onset have been reported so far. We report for the first time the neuropathological findings obtained from two foetuses harbouring deleterious variants in the EIF2B5 gene who presented in utero growth retardation and microcephaly with simplified gyral pattern that led to a medical termination of the pregnancy at 27 and 32 weeks of gestation. Neuropathological examination confirmed microcephaly with delayed gyration, periventricular pseudo-cysts and severe cerebellar hypoplasia. Histologically, the cerebellar cortex was immature, the dentate nuclei were fragmented and myelin stains revealed almost no myelination of the infratentorial structures. Bergmann glia was virtually absent associated to a drastic decreased number of mature astrocytes in the cerebellar white matter, multiple nestin-positive immature astrocytes as well as increased numbers of PDGRFα-positive oligodendrocyte precursors. Whole exome sequencing performed in the two foetuses and their parents allowed the identification of two EIF2B5 compound heterozygous variants in the two foetuses: c.468C > G p.Ile156Met and c.1165G > A p.Val389Met, the parents being heterozygous carriers. These variants are absent in the genome Aggregation Database (gnomAD r2.0.2). Contrary to the variant Ile156Met already described in a patient with CACH syndrome, the variant p.Val389Met is novel and predicted to be deleterious using several softwares. Neuropathological findings further expand the phenotypic spectrum of the disease that very likely occurs during early gestation and may manifest from the second half of pregnancy by a severe impairment of cerebral and cerebellar development.

TAR syndrome: Clinical and molecular characterization of a cohort of 26 patients and description of novel noncoding variants of RBM8A.

Thrombocytopenia-absent radius (TAR) syndrome is characterized by radial defect and neonatal thrombocytopenia. It is caused by biallelic variants of RBM8A gene (1q21.1) with the association of a null allele and a hypomorphic noncoding variant. RBM8A encodes Y14, a core protein of the exon junction complex involved in messenger RNA maturation. To date, only two hypomorphic variants have been identified. We report on a cohort of 26 patients affected with TAR syndrome and carrying biallelic variants in RBM8A. Half patients carried a 1q21.1 deletion and one of the two known hypomorphic variants. Four novel noncoding variants of RBM8A were identified in the remaining patients. We developed experimental models enabling their functional characterization in vitro. Two variants, located respectively in the 5'-untranslated region (5'-UTR) and 3'-UTR regions, are responsible for a diminished expression whereas two intronic variants alter splicing. Our results bring new insights into the molecular knowledge of TAR syndrome and enabled us to propose genetic counseling for patients' families.

Exome sequencing identifies the first genetic determinants of sirenomelia in humans.

Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio-based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2. We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.

Human interleukin-2 receptor ß mutations associated with defects in immunity and peripheral tolerance.

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) ß chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rß and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rß expression and function. IL-2Rß loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rß also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.

Bardet-Biedl syndrome: Antenatal presentation of forty-five fetuses with biallelic pathogenic variants in known Bardet-Biedl syndrome genes.

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.

Truncus arteriosus communis: report of three cases and review of literature.

BACKGROUND: Truncus arteriosus communis (TAC) is a congenital heart defect in which the physiologic arterial common trunk was not divided into aorta and pulmonary artery trunk. OBJECTIVES: In this paper, we report on three observed cases from which we looked for (in conjunction with literature review) the different causes of TAC many of which have genetic origins. METHODS: We collected three clinical files of fetuses having a TAC. Two of them were examinated after a medical termination of pregnancy motivated by severe cardiopathy. The malformation had been diagnosed based on different techniques: echocardiography, skeletal radiography, arteriography, fetal autopsy, karyotype and fluorescence in situ hybridization (FISH). RESULTS: Imaging and fetopathological examination revealed the presence of TAC type 3 and 4 in the Van Praaghs classification. FISH analysis showed a 22q11.2 deletion in one fetus in favour of Digeorge syndrome. The karyotype analysis performed in two cases was normal. CONCLUSION: Truncus arteriosus is a rare pathology caused by numerous etiologies from which many of them have genetic origin. This malformation can be diagnosed early during prenatal period. Postmortem fetopathological examination allows a better diagnosis approach and eventually a genetic counseling in recurrent cases such as case of consanguinity.

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-ß-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.

Early fetal presentation of Koolen-de Vries: Case report with literature review.

Koolen-de Vries syndrome (MIM#610443) is a rare microdeletion syndrome involving the 17q21.31 region, which was first described by Koolen in 2006. Clinical and behavioral characteristics have been extensively reported from more than 100 postnatal cases including infants, children and young adults. The syndrome is highly clinically heterogeneous, but the main features associate characteristic cranio-facial dysmorphism, heart defects, limb, skeletal, genito-urinary anomalies, along with intellectual disability with early childhood epilepsy and behavioral disturbances. Central nervous system malformations usually consist in hydrocephalus and thin corpus callosum. We report herein an early fetal case with an apparently isolated abnormal corpus callosum diagnosed by ultrasonography, for which a medical termination of the pregnancy was achieved at 22 weeks of gestation. Postmortem examination displayed facial dysmorphism consisting of hypertelorism, short philtrum and flat and broad nose, cleft palate and left duplex ureter. Neuropathological examination revealed a mega corpus callosum that has never been reported so far in this syndrome. Array-CGH performed on thymic DNA tissue revealed a 17q21.31 microdeletion, which allowed for the confirmation of early occurring Koolen-de Vries syndrome.

Fraser syndrome: features suggestive of prenatal diagnosis in a review of 38 cases.

OBJECTIVE: Fraser syndrome (FS) is a rare malformation recessive disorder. Major criteria are cryptophtalmos, syndactyly, respiratory, genital and urinary tract anomalies. Few prenatal presentations have been reported. METHOD: We analyzed the prenatal and postnatal fetal phenotype in 38 cases of FS, including 25 pregnancy termination cases, 8 intra-uterine death cases and 4 cases that died after birth. RESULTS: Including both prenatal and postnatal fetal phenotypic evaluation, all cases presented dysmorphic features with nose and ear dysplasia. Renal anomalies and syndactyly were present in 37/38 cases, cryptophtalmos in 36/38, airways anomalies in 30/37 and genital anomalies in 30/35 cases. Anomalies of the abdominal wall such as low set umbilicus and omphalocele were found in 31 cases. Among the 26 cases for which ultrasound data were available, detectable anomalies included oligohydramnios (22), ascites/hydrops (9), renal anomalies (20), evidence for high airways obstruction (11), ophthalmologic anomalies (4), ear dysplasia (2) and syndactyly (2). CONCLUSION: This study shows that the postnatal phenotype of FS is very specific, whereas oligohydramnios hampers the prenatal recognition of the cardinal FS diagnosis criteria. Association of oligohydramnios, kidney agenesis and CHAOS should lead to consider this diagnosis. © 2016 John Wiley & Sons, Ltd.

Prenatal Testicular Torsion: Not Always in the Late Third Trimester.

Prenatal testicular torsion is a very rare morbid entity, described in the literature to occur when the testicle is intrascrotal, around the 34th week of gestation. Here we report a case of early testicular necrosis. This male fetus was the product of a medical abortion at 27 weeks. During evisceration, a left testicular nubbin free in the peritoneal cavity was found. Histologically, it was extensively necrotic. Because of the location, the size, and the histological features of this necrotic testicle, we conclude that it was the result of torsion of the pedicle that occurred around the 20th week of pregnancy.

Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome.

KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.