Fetal anomalies associated with<i>HNF1B</i>mutations: report of 20 autopsy cases

Duval, Hélène; Michel-Calemard, Laurence; Gonzalès, Marie; Loget, Philippe; Bénéteau, Claire; Buénerd, Annie; Joubert, Madeleine; Denis-Musquer, Marielee; Clémenson, Alix; Chesnais, Anne-Laure; Blesson, Sophie; Pinieux, I. De; Delezoide, Anne‐Lise; Bonyhay, Gheorghe; Bellanné‐Chantelot, Christine; Heidet, Laurence; Dupré, Florence; Collardeau‐Frachon, Sophie

doi:10.1002/pd.4858

Cited by 30 publications

(29 citation statements)

References 23 publications

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“…CMA from the amniocentesis was sent with an indication of “echogenic kidneys.” The analysis revealed a 1.39Mb deletion at 17q12, which included two genes of note— HNF1B and LHX1 . Pathogenic variants and deletions in HNF1B (also referred to as TCF2 ) have been found in patients with renal cysts and diabetes syndrome . Deletion of LHX1 is associated with additional features including cognitive impairment, seizures, and structural brain abnormalities .…”

Section: Resultsmentioning

confidence: 99%

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Fetal phenotypes emerge as genetic technologies become robust

et al. 2019

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Prenatal genomic evaluation of the fetus is available at decreasing cost and with a faster turnaround time. However, fetal genotype‐phenotype correlations are in their infancy. By comparison, pediatric and adult genotype‐phenotype databases are well established and publicly accessible. A similar system for fetal genomics is lacking. When a fetal anomaly is identified by ultrasound imaging, a genetic diagnosis provides important information. However, fetal prognostic counseling is problematic if the only available information is based on outcomes following postnatal diagnoses. The same conditions identified prenatally may have more benign or more deleterious outcomes. Also, the condition may evolve over the pregnancy itself. As genomic testing increasingly examines fetal DNA at a single nucleotide level, the concomitant in utero phenotype deserves equal attention. Often, the reports of fetal phenotype are limited. Among sonologists, an increased awareness of attaining and communicating detailed fetal phenotypes is needed. The interpretation of expanded prenatal sequencing is reliant on deeper fetal phenotyping. The information gained significantly impacts clinical care and understanding of fetal development. This case series highlights: the broad spectrum of fetal phenotypes for known genetic conditions, phenotype progression during pregnancy, and the need to supplement systematic imaging with descriptive details when assessing fetuses with malformations.

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Section: Resultsmentioning

confidence: 99%

“…Pathogenic variants and deletions in HNF1B (also referred to as TCF2) have been found in patients with renal cysts and diabetes syndrome. [7][8][9] Deletion of LHX1 is associated with additional features including cognitive impairment, seizures, and structural brain abnormalities. 10 The deletion was considered to have clinical significance.…”

Section: Casementioning

confidence: 99%

Fetal phenotypes emerge as genetic technologies become robust

et al. 2019

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“…SNVs/indels described to date include nonsense, frameshift, splice‐site, and missense variants. The latter are mainly distributed within exons 2 to 4, which code for the DNA‐binding domain . All described HNF1B whole gene deletions so far correspond to chromosome 17q12 microdeletions spanning 1.3 to 1.8 Mb on average and including neighboring genes .…”

Section: Introductionmentioning

confidence: 99%

“…The latter are mainly distributed within exons 2 to 4, which code for the DNA-binding domain. 8,19,22,27 All described HNF1B whole gene deletions so far correspond to chromosome 17q12 microdeletions spanning 1.3 to 1.8 Mb on average and including neighboring genes. 10,28,29 Both intragenic variants and genomic rearrangements contribute almost equally to the HNF1Bassociated phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…Likewise, the herein reported prenatal identification of an intragenic HNF1B variant in individual I1 is likely a consequence of increased availability and demand for such NGS-based techniques. Because of the known high frequency of intragenic HNF1B variants in fetal autopsy cases8,19,27,56 or in postnatally diagnosed children with renal diseases,11,15,22,30,34,36 HNF1B mutation screening should be an integral part of prenatal diagnosis for hyperechogenic/multicystic kidneys.Customized targeted panels capturing multiple cystic kidney diseaserelated genes, like the one used herein, have several favorable features for the prenatal setting: high coverage, short turnaround times, and compatibility with small benchtop sequencing machines. Clinical exome sequencing (covers approximately 5000 to 7000 disease genes) is currently a reasonable compromise, although it requires more time and is less accessible.…”

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confidence: 99%

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Prenatal diagnosis of HNF1B‐associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

et al. 2019

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Objective 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies. Methods Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B‐related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. Results In a prenatal case, we identified a novel in‐frame deletion p.(Gly239del) within the HNF1B DNA‐binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B‐associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up‐to‐date overview of the mutational spectrum. Conclusions We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making.

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The diagnostic potential of targeted imaging of the fetal pancreas

et al. 2021

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Objective: To report our experience with targeted scans of the fetal pancreas.Methods: Targeted scans were performed in 16 cases referred for anatomical or genetic conditions associated with structural pancreatic malformations.Results: Four fetuses were evaluated for nephromegaly and macroglossia. In three of them, the pancreas circumference was >90th percentile. Genetic testing revealed Beckwith-Wiedemann syndrome. In the fourth case, the pancreas circumference was normal; exome sequencing revealed two heterozygous ETFDH gene mutations consistent with glutaric acidemia type II. In a case referred for non-visualization of the gallbladder, the fetal pancreas was not visualized and genetic analysis revealed a mutation in the ONECUT1 gene encoding for HNF6.Targeted scan for heterotaxia revealed three cases with variable degrees of agenesis of the pancreas, one case with a normally structured right sided pancreas and one case with a normal pancreas. Cases referred following a genetic diagnosis included a case of maternal nesidioblastosis with an extremely large fetal pancreas; and five fetuses diagnosed with a TCF2 deletion all with a normal pancreas.Conclusions: Prenatal assessment of the fetal pancreas may be a significant factor in prenatal diagnosis and counselling in cases presenting with anatomical and genetic conditions reported post-natally to be associated with pancreatic structural and functional abnormalities. Key PointsWhat's already known about this topic? � Structural aberrations of the pancreas have been reported in association with several congenital malformations and genetic syndromes � The prenatal literature regarding imaging of the fetal pancreas is scarce � Sonographic imaging of the fetal pancreas is feasible What does this study add?� Prenatal ultrasound may detect structural abnormalities of the fetal pancreas � Prenatal evaluation of the fetal pancreas has the potential to provide a more accurate prenatal phenotype and affect genetic testing and risk assessment in a wide spectrum of prenatal scenarios 828 -Prenatal Diagnosis.

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Fetal anomalies associated withHNF1Bmutations: report of 20 autopsy cases

Cited by 30 publications

References 23 publications

Fetal phenotypes emerge as genetic technologies become robust

Fetal phenotypes emerge as genetic technologies become robust

Prenatal diagnosis of HNF1B‐associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

The diagnostic potential of targeted imaging of the fetal pancreas

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