IntroductionAcute fetal leukemia is rare and characterized by a very poor prognosis. The aims of this study were to identify cases of acute fetal leukemia and to describe ultrasound and fetopathological findings that should lead to a suspicion of this diagnosis, as well as the investigations required to confirm it.MethodsA national retrospective study was conducted. Clinical data, prenatal ultrasounds and postmortem findings of fetal acute leukemia cases were collected and analyzed.ResultsWe collected seven cases: four in utero fetal deaths, two neonatal deaths and one termination of pregnancy. Prenatal ultrasounds showed fetal hydrops (42.9%) associated with hepatosplenomegaly (100%). In addition, post-mortem examination (n = 6) suggested a Down syndrome in one case and showed other organomegaly (83.3%) due to blastic infiltration, mainly in the liver, along with extrahepatic multivisceral hematopoiesis. Immunostainings allowed to specify the type of leukemia (71.4%). In one case, diagnosis was made on blood smear and flow cytometry was performed on fresh blood samples. All cases corresponded to acute myeloid leukemia. Karyotype was abnormal in 4 cases (66.7%), including one free trisomy 21, two mosaic trisomy 21 and one chromosome 15 deletion. GATA1 gene mutations were identified in two cases: one mosaic trisomy 21 and one with normal karyotype.ConclusionAny hepatosplenomegaly associated with fetal hydrops and a negative immune, infectious, and metabolic work-up, should suggest acute fetal leukemia and prompt additional investigations. What's already known about this topic?The diagnosis of acute fetal leukemia remains difficult, given the non-specific and heterogeneous presentation. It can only be suspected based on ultrasound and fetopathological examinations. The diagnosis of certainty is histological, based on the visualization of blasts, either circulating or infiltrating fetal organs.What does this study add?This study reviews the ultrasound and fetopathological findings that should lead to the diagnosis of acute fetal leukemia, which is all too often overlooked. It also underlines the importance of rigorous diagnostic methods and the essential additional investigations to be carried out.

INTRODUCTION:Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described. METHOD:After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases. RESULTS:We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots. CONCLUSION:Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.

Sexual development is a complex process relying on numerous genes. Disruptions in some of these genes are known to cause differences of sexual development (DSDs). Advances in genome sequencing allowed the discovery of new genes implicated in sexual development, such as PBX1. We present here a fetus with a new PBX1 NM_002585.3: c.320G>A,p.(Arg107Gln) variant, presenting with severe DSD along with renal and lung malformations. Using CRISPR-Cas9 gene editing on HEK293T cells, we generated a KD cell line for PBX1. The KD cell line showed reduced proliferation and adhesion properties compared with HEK293T cells. HEK293T and KD cells were then transfected plasmids coding either PBX1 WT or PBX1-320G>A (mutant). WT or mutant PBX1 overexpression rescued cell proliferation in both cell lines. RNA-seq analyses showed less than 30 differentially expressed genes, in ectopic mutant-PBX1-expressing cells compared with WT-PBX1. Among them, U2AF1, encoding a splicing factor subunit, is an interesting candidate. Overall, mutant PBX1 seems to have modest effects compared with WT PBX1 in our model. However, the recurrence of PBX1 Arg107 substitution in patients with closely related phenotypes calls for its impact in human diseases. Further functional studies are needed to explore its effects on cellular metabolism.

Defects in L-serine biosynthesis are a group of autosomal recessive diseases resulting in a wide phenotypic spectrum ranging from viable to lethal presentations and caused by variants in the three genes encoding the L-serine biosynthesis enzymes, PHGDH, PSAT1, and PSPH. Neu-Laxova syndrome (NLS) is the fetal form of this group, characterized by multiple congenital anomalies including severe intrauterine growth retardation, cutaneous lesions extending from ichthyosis to severe restrictive dermopathy with ectropion and eclabion, edema, microcephaly, central nervous system abnormalities, and flexion contractures. Here we report on two unrelated fetuses with an attenuated phenotype of NLS, that initially evoked Taybi-Linder syndrome. They carry biallelic pathogenic variants in the PHGDH gene. These observations expand the phenotypic continuum of L-serine biosynthesis defects, and illustrate the phenotypic overlap between NLS and microcephalic primordial dwarfism.

Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.

Objective: To better understand the physiology of pain in pelvic pain pathological conditions, such as endometriosis, in which alter-ations of uterine innervation have been highlighted, we performed an anatomic and functional mapping of the macro-and microin-nervation of the human uterus. Our aim was to provide a 3-dimensional reconstruction model of uterine innervation. Design: This was an experimental study. We dissected the pelvises of 4 human female fetuses into serial sections, and treated them with hematoxylin and eosin staining before immunostaining. Setting: Academic Research Unit. Patients: None. Interventions: None. Main outcome measures: Detection of nerves (S100 +) and characterization of the types of nerves. The slices obtained were aligned to construct a 3-dimensional model. Results: A 3-dimensional model of uterine innervation was constructed. The nerve fibers appeared to have a centripetal path from the uterine serosa to the endometrium. Within the myometrium, innervation was dense. Endometrial innervation was sparse but present in the functional layer of the endometrium. Overall innervation was richest in the supravaginal cervix and rarer in the body of the uterus. Innervation was rich particularly laterally to the cervix next to the parametrium and paracervix. Four types of nerve fibers were identified: autonomic sympathetic (TH+), parasympathetic (VIP+), and sensitive (NPY+, CGRP1+ and VIP+). They were found in the 3 portions and the 3 layers of the uterus. Conclusions: We constructed a 3-dimensional model of the human uterine innervation. This model could provide a solid base for studying uterine innervation in pathologic situations, in order to find new therapeutic approaches. (C) 2022 by American Society for Reproductive Medicine.

Differences of sex development (DSDs) are a group of congenital conditions characterized by a discrepancy between chromosomal, gonadal, and genital sex development of an individual, with significant impact on medical, psychological and reproductive life. The genetic heterogeneity of DSDs complicates the diagnosis and almost half of the patients remains undiagnosed. In this context, chromosomal imbalances in syndromic DSD patients may help to identify new genes implicated in DSDs. In this study, we aimed at describing the burden of chromosomal imbalances including submicroscopic ones (copy number variants or CNVs) in a cohort of prenatal syndromic DSD patients, and review their role in DSDs. Our patients carried at least one pathogenic or likely pathogenic chromosomal imbalance/CNV or low-level mosaicism for aneuploidy. Almost half of the cases resulted from an unbalanced chromosomal rearrangement. Chromosome 9p/q, 4p/q, 3q and 11q anomalies were more frequently observed. Review of the literature confirmed the causative role of CNVs in DSDs, either in disruption of known DSD-causing genes ( SOX9, NR0B1, NR5A1, AR, ATRX,… ) or as a tool to suspect new genes in DSDs ( HOXD cluster, ADCY2, EMX2, CAMK1D,… ). Recurrent CNVs of regulatory elements without coding sequence content (i.e. duplications/deletions upstream of SOX3 or SOX9 ) confirm detection of CNVs as a mean to explore our non-coding genome. Thus, CNV detection remains a powerful tool to explore undiagnosed DSDs, either through routine techniques or through emerging technologies such as long-read whole genome sequencing or optical genome mapping.

La région chromosomique 22q11 est sujette à des variations du nombre de copies (CNV) récurrents en raison de la présence d’un grand nombre de séquences répétées (LCR). Les duplications typiques de cette région sont localisées entre les LCR-A et D, mais des duplications atypiques de taille variable sont également rapportées. Ces duplications sont responsables de phénotypes variables de pénétrance incomplète et d’expressivité variable, rendant le conseil génétique difficile en prénatal. Ce travail a pour but de mieux définir les phénotypes prénataux associés à ces duplications, en réalisant une revue de la littérature et en rapportant douze nouveaux cas (9 fœtus et 3 nouveau-nés décédés) diagnostiqués par ACPA (Analyse Chromosomique par Puce à ADN). Dans 60 % de ces cas, la duplication 22q11 est héritée d’un parent en apparente bonne santé. Un second CNV est identifié dans 8 % des cas. Les principaux signes cliniques observés incluent une hyperclarté nucale et des cardiopathies variées, ainsi que des atteintes squelettiques et rénales modérées. Les duplications de la région située entre les LCR-C et D (contenant CRKL) [1] sont plus fréquemment retrouvées chez les fœtus présentant une cardiopathie ou des anomalies rénales. Les fentes labio-palatines sont principalement observées chez les fœtus présentant des duplications de la région située entre les LCR-A et B ou impliquant le gène SPECC1L [2]. Il est difficile d’établir des corrélations génotype-phénotype plus précises. L’existence de variations génétiques ponctuelles (SNP), de variations épigénétiques [3] ou l’influence de facteurs environnementaux [4] peuvent expliquer la variabilité phénotypique des duplications 22q11, mais l’identification de ces facteurs reste difficile à réaliser au cours de la grossesse.

The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications encompass the LCR-A-to-D region but atypical duplications of various sizes have also been reported. These duplications are responsible for highly variable phenotypes with incomplete penetrance and expressivity, which is challenging for adequate genetic counselling, especially in the prenatal period. To better delineate prenatal phenotypes associated with these CNVs, we report here a clinical and molecular description of twelve cases (9 foetuses and 3 deceased new-borns babies) carrying recurrent 22q11 duplications (diagnosed via aCGH), along with a review of the existing literature. 22q11 duplications were inherited from an apparently healthy parent in almost 60% of the cases. Other CNVs were diagnosed for 8% of the cases. Increased nuchal translucency and cardiac anomalies (CHD) were the most prominent phenotypes observed, along with mild renal and skeletal anomalies. Duplications encompassing the LCR-C-to-D region (and the CRKL gene) seemed more likely to generate CHDs and renal malformations. Cleft lip/palate were observed in foetuses with duplications encompassing the LCR-A-to-B region or the SPECC1L gene, as previously suggested. However, genotype-phenotype correlations remain difficult to ascertain. Second-hit point variants, epigenetic or environmental variations could play a role in the phenotypic variability of 22q11 duplications, but remain a challenge for assessment in the short period of pregnancy.

Fetal mosaicism for chromosomal rearrangements remains a challenge to diagnose, even in the era of whole-genome sequencing. We present here a case of fetal mosaicism for a chromosomal rearrangement explored in amniocytes and fetal muscle, consisting of a major cell population (95%) with partial monosomy 4q and a minor population (5%) with additional material replacing the 4qter deleted segment. Molecular techniques (MLPA, array-CGH) failed to assess the origin of this material. Only multicolor-FISH identified the additional segment on chromosome 4 as derived from chromosome 17. Due to the poor prognosis, the couple chose to terminate the pregnancy. Because of low-level mosaicism, chromosomal microarray analysis (CMA), now considered as first-tier prenatal genetic analysis, did not allow the identification of the minor cell line. In case of large CNVs (>5 Mb) detected by CMA, karyotyping may be considered to elucidate the mechanism of the underlying rearrangement and eliminate mosaicism.

Objective Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed. Methods Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed. Results Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported). Conclusion The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome. Classification of Evidence This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.

Les anomalies du développement sexuel (DSD) sont des malformations congénitales complexes résultant en une discordance entre sexe chromosomique, gonadique et anatomique. À ce jour, dans les DSD, de nombreux patients restent encore sans diagnostic. Les résultats du séquençage d'exome d'un fœtus atteint de DSD syndromique a permis de mettre en évidence l'implication d'un nouveau gène, PBX1, dans le développement sexuel. Un fœtus mort-né a été adressé pour examen fœtopathologique pour syndrome polymalformatif (retard de croissance intra-utérin, DSD, rein droit pelvien). Le développement gonadique a été étudié par immunohistochimie (OCT4, CD117, SF1, FOXL2, inhibine). Les études génétiques ont inclus caryotype, FISH, ACPA et séquençage d'exome. Une étude par immunofluorescence ciblant PBX1 sur tissu congelé a été réalisée. Le fœtus présentait une hypotrophie rénale bilatérale avec rein droit pelvien, une hypoplasie pulmonaire et une dysgénésie gonadique (gonade de type testiculaire à droite, streak gonad à gauche) associée à la présence de dérivés wolffiens et müllériens, un tubercule génital proéminent, un hypospadias, des bourrelets génitaux non fusionnés. L'ACPA était normale. Caryotype et FISH ont montré un résultat 46,XY. L'exome retrouvait un variant hétérozygote de novo dans le gène PBX1 : p.(Arg107Gln). L'étude en immunofluorescence montrait une localisation nucléaire (normale) de PBX1, comparable aux témoins. PBX1 code pour un facteur de transcription fonctionnant en complexe protéique avec certaines protéines dont HOX [1]. Les dysfonctions de cette protéine ont été impliquées dans les anomalies rénales et urinaires syndromiques (CAKUT) [2]. Cinq cas ont été associés à des DSD, principalement chez des patients 46,XY, dont deux cas présentant une substitution touchant l'arginine 107 [PBX1 : p.(Arg107Trp)] [3], [4], [5]. D'autres études fonctionnelles sont en cours. PBX1, facteur de transcription impliqué dans les CAKUT syndromiques, joue un rôle majeur dans la différenciation gonadique et la masculinisation des individus 46,XY.

PURPOSE:Molecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.METHODS:We performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.RESULTS:sES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).CONCLUSIONS:This method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.

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Les microremaniements récurrents 16p11.2 situés entre BP4 et BP5 (550–600 kb) sont associés aux troubles du spectre autistique, neuro-développementaux et à la schizophrénie [1]. Néanmoins, une forte variabilité d’expression est décrite, surtout en cas de microduplication [2]. Les signes d’appel échographiques (SAE) et la conduite à tenir en cas d’identification d’un tel microremaniement en période prénatale sont peu documentés. Entre 2009 et 2018, le service de cytogénétique du CHU de Rennes a réalisé environ 1200 analyses chromosomiques sur puce à ADN en prénatal chez des fœtus à caryotype normal, ce qui a permis l’identification de cinq microremaniements 16p11.2 (5/1200 soit 0,4 %). Quatre microduplications 16p11.2 ont été observées chez des fœtus présentant respectivement un arc aortique droit (1), un hydramnios (2), un RCIU associé à un rhombencephalosynapsis (3), des fémurs et humérus courts associés à des anomalies des organes génitaux externes (4). Chez les fœtus 1 et 2, un autre diagnostic génétique pouvait expliquer les SAE observés : microdélétion 22q11.21 impliquant TBX1 chez le fœtus 1 et syndrome de Steinert congénital chez le fœtus 2. Le microremaniement était hérité d’un parent en bonne santé chez les fœtus 1 et 3, de novo chez le fœtus 2 et l’enquête familiale n’a pas été réalisée pour le fœtus 4. Par ailleurs, une microdélétion 16p11.2 héritée de la mère a été identifiée chez un fœtus présentant un hygroma colli (5). Un cas d’hyperclarté nucale isolée a précédemment été rapporté dans une série de 12 fœtus porteurs de cette microdélétion 16p11.2 [3]. À notre connaissance, aucune étude ne s’est intéressée spécifiquement aux microduplications. Le manque de données cliniques associé à la grande variabilité d’expression rend le conseil génétique difficile. Une étude sur une plus large cohorte de fœtus est nécessaire pour mieux appréhender l’impact de ces microremaniements 16p11.2.

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.

Il existe au niveau de la région proximale du bras long du chromosome 22 huit low copy repeat (LCR22) favorisant les recombinaisons et la survenue de remaniements chromosomiques. La microduplication typique 22q11.2 montre une expressivité très variable et une pénétrance incomplète, ayant rendu sa découverte tardive et son étude complexe. Des duplications atypiques, conséquence d’anomalies de recombinaison dans des LCR alternatifs, surviennent de façon plus rare, avec de ce fait des conséquences phénotypiques moins bien identifiées. Nous présenterons 6 cas de duplications 22q11.2 atypiques, identifiées par analyse chromosomique sur puce à ADN, après examen fœtopathologique. Elles correspondent à deux duplications d’1.3 Mb LCR22-F/LCR22-H (agénésie thymique dans un cas, hygroma colli et cardiopathie dans l’autre cas), une duplication d’1.2 Mb LCR22-D/LCR22-E survenue de novo (hypertrophie rénale bilatérale et anomalies digitales), une duplication d’1,8 Mb LCR22-E/LCR22-H héritée du père (dysmorphie faciale, cardiopathie et agénésie rénale), une duplication de 745 kb LCR-B/LCR-D héritée du père (tableau polymalformatif) et une duplication de 400 kb LCR-C/LCR-D (clarté nucale augmentée en échographie). Par ailleurs, 6 cas de duplication 22q11.2 typiques ont été identifiés chez des fœtus présentant un phénotype variable avec souvent une cardiopathie congénitale. Notre étude permet de préciser la description du phénotype fœtal associé aux microduplications 22q11.2, typiques et atypiques. L’implication de ces duplications 22q11.2 mais aussi de facteurs moléculaires additionnels permettant d’expliquer le phénotype est discutée. Par ailleurs, grâce à l’apport des techniques de séquençage massif en parallèle (MPS), des variants géniques pathogéniques ont récemment été identifiés chez des patients présentant une duplication 22q11.21 et une présentation clinique atypique ou très sévère, démontrant l’utilité de rechercher un deuxième évènement moléculaire dans ces cas [1]. Cette approche complémentaire par MPS est conseillée pour les variations du nombre de copies d’ADN à pénétrance incomplète, afin d’aider à la réalisation d’un conseil génétique plus précis.

This is a case report of a disseminated fetal rhabdoid tumor discovered at 32 weeks of gestation in a 29-year-old woman on immunosuppressive therapy. The mother consulted for a decrease in fetal movement. Fetal ultrasound showed signs of a disseminated tumor affecting the left armpit, liver, spleen, and limbs. A caesarian section was performed because of signs of fetal distress. Immunohistochemical analysis of a fetal biopsy showed deletion of the SMARCB1 gene. Pathological analysis of the placenta showed a rhabdoid tumor invading both fetal and maternal compartments. The mother underwent a whole-body MRI, and no metastasis was found. To the best of our knowledge, this is the first report of a disseminated rhabdoid tumor invading both fetal and maternal compartments.

We report a multiplex family with a GATA1 gene mutation responsible for a massive fetal cerebral hemorrhage occurring at 36 weeks. Two other stillbirth cousins presented with fetal hydrops and congenital hemochromatosis' phenotype at 37 and 12 weeks of gestation. Molecular screening revealed the presence of a c.613G>A pathogenic allelic variation in exon 4 of GATA1 gene in the 3 male siblings and their carrier mothers. The diagnosis of a GATA1 gene mutation may be suspected in cases of male fetuses with intracerebral bleeding, particularly if a history of prior fetal loss(es) and mild maternal thrombocytopenia are also present.

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.