Whole exome sequencing improves genetic diagnosis of fetal clubfoot

Huang, Ruibin; Zhou, Huayun; Ma, Chunling; Fu, Fang; Cheng, Ken; Wang, You; Li, Ru; Lei, Tingying; Yu, Qiuxia; Wang, Dan; Yan, Shujuan; Yang, Xin; Li, Dong-Zhi; Liao, Can

doi:10.1007/s00439-022-02516-y

Cited by 8 publications

(9 citation statements)

References 57 publications

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“…Diagnostic genetic work‐up is indicated upon discovery of HEK, whether isolated or non‐isolated. Several case series have been published in recent years describing molecular and cytogenetic analysis among fetuses with HEK 2–4,9,11,14–16 . Among fetuses with isolated bilateral HEK, the most commonly identified etiologies include ARPKD, ADPKD, and HNF1b ‐related intra‐genic variants or CNVs at locus 17q12 encompassing HNF1b .…”

Section: Etiology Of Echogenic Kidneysmentioning

confidence: 99%

“…The critical gene at this locus, which is associated with a renal dysplasia phenotype, is HNF1b (OMIM #137920; alternative gene name TCF2 ). Among studies of HEK which performed SNP microarray analysis, incidence of 17q12 microdeletions and/or HNF1b disease‐causing variants ranges from 2% to 30% 3,4,14 . A recurring deletion at 17q12 is most commonly 1.4 Mb, though there are deletions reported of a larger size (e.g.…”

Section: Etiology Of Echogenic Kidneysmentioning

confidence: 99%

“…Among non‐isolated HEK, trisomy 13 is the most common 10 ; the fetal renal presentation may be echogenic at first, and cystic later 15 . Non‐isolated HEK has also been documented in trisomy 21 4,10 and 45, X 40 . There are a few reports of apparently isolated HEK in fetuses with aneuploidy, including a case of trisomy 13, 4 and two cases of trisomy 21 16 ; a fetus with monosomy X was reported to have echogenic and multicystic dysplastic kidneys and no extra‐renal anomalies 4,16,40 .…”

Section: Etiology Of Echogenic Kidneysmentioning

confidence: 99%

“…Non‐isolated HEK has also been documented in trisomy 21 4,10 and 45, X 40 . There are a few reports of apparently isolated HEK in fetuses with aneuploidy, including a case of trisomy 13, 4 and two cases of trisomy 21 16 ; a fetus with monosomy X was reported to have echogenic and multicystic dysplastic kidneys and no extra‐renal anomalies 4,16,40 . Less common chromosomal aberrations can present with HEK, often with evident multi‐system involvement 2,16,40,43–46 …”

Section: Etiology Of Echogenic Kidneysmentioning

confidence: 99%

“…A significant challenge befalls the clinician attempting to counsel families, as the sonographic presentation is only sometimes able to inform and narrow this prognostic spectrum. Among published series with larger cohorts, approximately 25% of cases present as apparently‐isolated HEK, while approximately 75% of cases are non‐isolated, presenting with other renal or extra‐renal anomalies 2–4 …”

Section: Introductionmentioning

confidence: 99%

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Fetal hyperechoic kidneys: Diagnostic considerations and genetic testing strategies

Hertenstein,

Miller,

Estroff

et al. 2024

Prenatal Diagnosis

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Isolated bilateral hyperechoic kidneys (HEK) on prenatal ultrasound presents diagnostic, prognostic, and counseling challenges. Prognosis ranges from normal outcome to lethal postnatally. Presence/absence of extra‐renal malformations, gestational age at presentation, amniotic fluid volume, and renal size may distinguish underlying etiologies and thereby prognosis, as prognosis is highly dependent upon underlying etiology. An underlying genetic diagnosis, clearly impactful, is determined in only 55%–60% of cases. We conducted a literature review of chromosomal (aneuploidies, copy number variants [CNVs]) single genes and other etiologies of fetal bilateral HEK, summarized how this information informs prognosis and recurrence risk, and critically assessed laboratory testing strategies. The most commonly identified etiologies are autosomal recessive and autosomal dominant polycystic kidney disease and microdeletions at 17q12 involving HNF1b. With rapid gene discovery, alongside advances in prenatal imaging and fetal phenotyping, the growing list of single gene diagnoses includes ciliopathies, overgrowth syndromes, and renal tubular dysgenesis. At present, microarray and gene panels or whole exome sequencing (WES) are first line tests employed for diagnostic evaluation. Whole genome sequencing (WGS), with the ability to detect both single nucleotide variants (SNVs) and CNVs, would be expected to provide the highest diagnostic yield.

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Section: Etiology Of Echogenic Kidneysmentioning

confidence: 99%

Section: Etiology Of Echogenic Kidneysmentioning

confidence: 99%

Section: Etiology Of Echogenic Kidneysmentioning

confidence: 99%

Section: Etiology Of Echogenic Kidneysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fetal hyperechoic kidneys: Diagnostic considerations and genetic testing strategies

Hertenstein,

Miller,

Estroff

et al. 2024

Prenatal Diagnosis

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When should we offer antenatal sequencing for urinary tract malformations? A systematic review, cohort study and meta‐analysis

Sonner,

Reilly,

Woolf

et al. 2023

Prenatal Diagnosis

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ObjectiveDetermine the incremental yield of prenatal exome sequencing (PES) over chromosome microarray (CMA) and/or karyotype for urinary tract malformations (UTMs).MethodA prospective cohort study encompassing data from the English Genomic Medicine Service North Thames Laboratory Hub for fetuses with bilateral echogenic kidneys (BEKs) was combined with data from a systematic review. MEDLINE, EMBASE, Web of Science, MedRxiv and GreyLit were searched from 01/2010‐02/2023 for studies reporting on the yield of PES over CMA or karyotype in fetuses with UTMs. Pooled incremental yield was determined using a random effects model. PROSPERO CRD42023364544.ResultsFourteen studies (410 cases) were included. The incremental yield for multisystem UTMs, any isolated UTMs, and BEKs was 31% [95% CI, 18%–46%; I2 = 78%], 16% [95% CI, 6%–26%; I2 = 80%] and 51% [95% CI, 27%–75%; I2 = 34%]. The most common clinical diseases and syndromes identified, based on the variant genes detected, were Bardet‐Biedl syndrome (BBS genes), dominant and recessive polycystic kidney diseases (PKD1, PKD2 and PKHD1) and renal cysts and diabetes syndrome (HNF1B).ConclusionThere was a notable incremental genetic diagnostic yield when PES was applied to multisystem UTMs and BEKs. There was a modest incremental yield when this technique was used for UTMs other than BEKs.

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Prenatal diagnosis of polycystic renal diseases: diagnostic yield, novel disease-causing variants, and genotype–phenotype correlations

Huang,

Fu,

Guo

et al. 2024

American Journal of Obstetrics & Gynecology MFM

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Whole exome sequencing improves genetic diagnosis of fetal clubfoot

Cited by 8 publications

References 57 publications

Fetal hyperechoic kidneys: Diagnostic considerations and genetic testing strategies

Fetal hyperechoic kidneys: Diagnostic considerations and genetic testing strategies

When should we offer antenatal sequencing for urinary tract malformations? A systematic review, cohort study and meta‐analysis

Prenatal diagnosis of polycystic renal diseases: diagnostic yield, novel disease-causing variants, and genotype–phenotype correlations

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