The genetic etiologies of bilateral renal agenesis

Abstract

Objective:

The goal of this study was to review and analyze the medical literature for cases of prenatal and/or postnatally diagnosed bilateral renal agenesis (BRA) and create a comprehensive summary of the genetic etiologies known to be associated with this condition.

Methods:

A literature search was conducted as a scoping review employing OMIM, PubMed, and Cochrane to identify cases of BRA with known underlying genetic (chromosomal versus single gene) etiologies and those described in syndromes without any known genetic etiology. The cases were further categorized as isolated versus non-isolated, describing additional findings reported prenatally, postnatally, and postmortem. Inheritance pattern was also documented when appropriate in addition to reported timing of diagnosis, and sex.

Results:

We identified 6 cytogenetic abnormalities, and 21 genes responsible for 20 single gene disorders associated with BRA. Five genes have been reported to associate with BRA without other renal anomalies; sixteen others associate with both BRA as well as unilateral renal agenesis (URA). Six clinically recognized syndromes/associations were identified with yet unknown underlying genetic etiology. Genetic etiologies of BRA are often phenotypically expressed as other urogenital anomalies as well as complex multi-system syndromes.

Conclusion:

Multiple genetic etiologies of BRA have been described including cytogenetic abnormalities and monogenic syndromes. The current era of utilization of exome and genome-wide sequencing is likely to significantly expand our understanding of the underlying genetic architecture of BRA.

Introduction

Bilateral renal agenesis (BRA) is a congenital anomaly detected on a fetal anatomic survey by the documentation of absent renal tissue, generally diagnosed sonographically at 18-22 weeks gestation. BRA reportedly occurs in 1 in 7,700 fetuses to 30,000 live births (1, 2) and although often seen in isolation, may be but one feature of a complex genetic syndrome affecting other organ systems. BRA is complicated by anhydramnios which limits its detection as well as the detection of anomalies in other organ systems on ultrasound. Importantly, BRA must be differentiated from mimickers including multicystic dysplastic kidney (MCDK) and renohypodysplasia (RHD). Small dysplastic kidneys may be overlooked on prenatal ultrasound, especially if ectopic. Urinary tract obstruction can lead to RHD leading to kidney involution, which may help explain the higher prevalence of BRA in males compared to females. The ability to delineate isolated BRA from complex BRA is becoming increasingly important in the era of the Renal Agenesis Fetal Therapy Trial (3–5).

BRA is one of multiple renal pathologies included under the umbrella of CAKUT, an acronym coined for Congenital Anomalies of the Renal and Urinary Tract, which taken altogether are present in approximately 0.1 to >1.0 of births (1, 6, 7). Historically, BRA has long been noted to have a preponderance for male sex, with an autopsy study initially reporting approximately three fourths of cases male and one fourth female (8). With improved molecular investigative methods that include massive parallel sequencing, many genes have now been identified as causative in CAKUT. There are comparatively more data on the genetics of unilateral renal dysgenesis and dysplasia compared to BRA, however postnatal cohorts of BRA are scarce due to lethality and thus large exome studies have yet to be published.

Prognostic counseling in CAKUT is dependent upon the renal anomaly as well as presence of extrarenal anomalies. BRA has a perinatally lethal natural course due to early onset anhydramnios and the resulting lung hypoplasia. Renal agenesis is often isolated, but most of its underlying genes are associated with other genitourinary anomalies given their common embryological origin of the urogenital ridge (9, 10), or with extra-renal anomalies consequent to a common developmental pathogenic pathway (11–13). Known genetic disruptions may affect the development of and signaling between the ureteric bud and the mesonephric duct or the metanephric mesenchyme, or disrupt basic internal kidney development and tubulogenesis (1, 14). Murine models have confirmed the role of specific genes during embryogenesis. (15–17).

An associated genetic disorder should be considered for both isolated and complex BRA; there are many reported in the literature, either through case reports or larger case series. Cytogenetic full or partial aneuploidies generally have additional sonographic findings. Likewise, the single gene disorders associated with BRA have additional characteristics that may distinguish them from one another. BRA appears to be more prevalent in males than in females which is only partially attributable to X-linked single gene disorders (11). In addition, there are recognized clinical syndromes associated with BRA for some of which an underlying genetic etiology seems evident by e.g. pedigree analysis but a gene has not yet been identified. The objective of this clinical review is to summarize the pathogenetic etiologies of BRA through the use of OMIM, PubMed, and the Cochrane database. While several sizable studies of CAKUT have described over 287 implicated genes (12, 13, 18), only one has focused specifically on BRA (17), and one on unilateral renal agenesis (URA) (19). Some include renal agenesis, but have no cases specifically delineated as bilateral, and none have included cases of recognized genetic syndromes for which the gene responsible remains unknown.

Methods

The authors, with the assistance of a professional medical librarian, carried out a review of 3 electronic databases: OMIM, PubMed, and Cochrane. These were interrogated for genes associated with BRA published between 1975 and 2023. The search string used, reviewed by the medical librarian, was comprised of “bilateral renal agenesis”, “bilateral renal agenesis genes” and MESH terms “CAKUT”, “gene” and “trisomy”. Published original articles inclusive of case reports, case series, clinical studies, meta-analyses, and systematic review articles were considered, with the final search performed on October 6, 2023. Genes citied in review articles were individually assessed and compared to ensure all relevant genes were included. The search was refined by including only cases of single gene variants, chromosomal abnormalities, established genetic syndromes, and associations. Three investigators (GWK, GF and ACJ) screened the abstracts, there was no disagreement, and ACJ approved the included articles.

Study Selection

In addition to the above, study inclusion criteria were as follows: 1) English language with access to full text, 2) renal genotype/phenotype clearly documented and consistent with BRA (i.e. other pathology such as renal hypoplasia was excluded unless it was clearly documented that at least one case involving BRA was associated with the genetic abnormality), 3) the gene was reported in a human subject and demonstrated ACMG P and LP variants (not susceptibility-only genes) (20), and 4) results were generated from an original case report, case series, or other research publication. Studies were excluded if the genotype/phenotype could not be confirmed. Reference articles generated by the database were then evaluated for cases meeting inclusion criteria.

Genotype and phenotype information was extracted from OMIM, PubMed and Cochrane. In addition, information on fetal sex, race, reported timing of diagnosis, and consanguinity was recorded when available. While racial demographics for reports of BRA were globally represented, due to underreporting in published larger case series, meaningful analysis could not be performed.

Results

Search strategy results

The OMIM search returned 41,281 entries with a clinical synopsis and the PubMed search returned 811 results. The Cochrane database returned 5 results involving diagnosis without notation of specific genes or syndromes, thus these were not included.

Out of the 41,281 articles originally identified, the majority were excluded due to the lack of genotype-phenotype correlation, or for representing cases of URA only without any known clinical cases of BRA, thus yielding a total of 2097 entries which were further screened for appropriateness, finally resulting in 63 articles included which met all study criteria. In addition, many mouse genes were identified without documentation of pathology in the correlated human genes, which were not considered.

Upon completion 6 cytogenetic abnormalities were identified, all of which were either complete, mosaic, or partial trisomies: including trisomy 13, trisomy 22, trisomy X, mosaic trisomy 7, mosaic trisomy 11, and partial trisomy 15q (Table 1). In addition, 20 different single gene disorders with a total of 21 corresponding genes were identified (Table 2; all genes are listed alphabetically in the table). Only five genes have been reported in cases with only BRA but not URA, while 16 of the genes were identified in cases with URA or BRA. Of note, the spectrum of renal anomalies previously reported to be associated with many of the identified genes was not limited to BRA, neither within the “BRA only” category or within the “BRA or URA” category, and often included additional renal conditions such as multicystic or dysplastic kidney disease. Six clinically recognized syndromes/associations were identified whose genetic etiology is unknown at the time of this writing (Table 3).

Table 1.

Cytogenetic abnormalities associated with bilateral renal agenesis

Syndrome	Locus	Additional Phenotype	Reported Timing of Diagnosis	Sex (M:F)	Reference
Patau Syndrome	Trisomy 13	Cleft lip/palate, brain, ocular, skeletal, cardiac	Prenatal		Chen (1999)(103) Phadke (2004)(104)
Trisomy 22	Trisomy 22	Growth restriction, webbed neck, craniofascial dysmorphism, microcephaly, cardiac, limb malformations	Prenatal		Van Buggenhout (1995)(105)
Trisomy X	Trisomy X	Hypertelorism		0:1	Hogge (1989)(106)
Mosaic Trisomy 7	Mosaic Trisomy 7	Skeletal, urogenital	Postmortem	0:1	Pflueger (1984)(107)
Mosaic Trisomy 11	Trisomy 11		Postmortem		Balasubramanian (2011)(108)
Partial Trisomy 15q	15q25.3 dup	Skeletal	Postnatal	1:0	Tatton-Brown (2009)(109) Froster (2000)(110)

Table 2.

Known single gene disorders that have been associated with Bilateral Renal Agenesis

Disorder	OMIM	Locus	Gene	Inheritance Pattern	Renal Phenotype	Additional Phenotype†	Reported Timing of Diagnosis	Sex (M:F)	Reference
Kallman Syndrome	308700	Xp22.31	ANOS1 (KAL1)	XLR	BRA, URA, renal pelviectasis	Craniofacial anomalies, urogenital, hypogonadotropic hypogonadism, impaired smell	Prenatal	2:0	Kirk (1994)(38) Albuisson (2005)(37) Smogavec 2022(39)
BICC1-associated renal disease	614295	10q21.1	BICC1 #	AD	BRA, cystic renal dysplasia	Myelomeningocele	Prenatal	Unknown	Jordan 2022(12) Kraus 2012(27)
Multinucleated neurons, anhydramnios, renal dysplasia, cerebral hypoplasia, and hydranencephaly (MARCH)	236500	10q23	CEP55 #	AR	BRA, ureteral, bladder agenesis/hypoplasia; dysplastic kidneys	Hydranencephaly, cerebellar hypoplasia	Postmortem	Unknown	Hamby (1950)(29) Strauss (1984)(28) Rawlins (2019)(30)
Branchio-oto-renal Syndrome 1 (Melnick-Fraser syndrome)	113650	8q13.3	EYA1	AD	BRA, URA unilateral UPJ obstruction, unilateral hypodysplasia	Skeletal, ear, hearing loss, urogenital, cardiothoracic, thymus malformations	Prenatal, Postnatal, Postmortem	1:1 1:0	Carmi (1983)(111) Hwang (2014)(90) Olavarrieta (2008)(49) Sanggarrd (2007) (50)
Renal Hypodysplasia/ Aplasia 2	615721	8p22	FGF20 #	AR	BRA	Urogenital, cardiothoracic, skeletal	Prenatal	4:0	Barak (2012)(22)
Antley-Bixler syndrome	207410	10q26.13	FGFR2	AR, AD	BRA, URA	Urogenital, skeletal, midface hypoplasia	Prenatal	1:0	LeHeup (1995), Le Bard (1998)(41, 112)
Fraser syndrome	219000	13q13.3, 4q21.21	FRAS1, FREM2	AR	BRA, URA	Urogenital, cardiothoracic, hand malformation, cerebral, skeletal anomaly	Prenatal Post-mortem	2:7	Shafeghati (2008)(46) Lurie (1984)(113) Burn (1982)(114) Mortimer (1985)(115) Stevens (1994)(116) Pankau (1994)(117) Amr (1996)(118)
GDNF receptor alpha-1	601496	10q25.3	GFRA1 #	AR	BRA	Hirschsprung disease		Unknown	Al-Shamsi (2022) (23) Arora (2021) (24)
Pallister-Hall Syndrome	146510	7p14.1	GLI3	AD	BRA, URA, renal hypoplasia/dysplasia	Urogenital, skeletal, polydactyly, bifid epiglottis, laryngotracheal cleft, hypothalamic hamartoma, pituitary insufficiency	Prenatal	0:1	McPherson (2013)(119) McClelland 2022 (120)
Renal Hypodysplasia/Aplasia 3	617805	18q11	GREB1L	AD	BRA, URA	Urogenital, skeletal, ear, MRKH1***	Prenatal	Unknown	De Tomasi (2017)(17) Sanna-Cherchi (2017)(54)
Neurofacioskeletal syndrome with or without renal agenesis (NFSRA)	619194	1p22.3	HS2ST1	AR	BRA, URA	Cerebral malformation, facial dysmorphism, skeletal	Prenatal	Unknown	Schneeberger (2020) (59)
Renal Hypodysplasia/ Aplasia 1	191830	10p13	ITGA8	AR	BRA, URA, renal aplasia, renal dysplasia, renal hypoplasia, polycystic, multicystic kidneys	Urogenital, cardiothoracic, hand malformation, skeletal anomaly	Prenatal25,29 Post-mortem24,26,27,28	66:26	Potter (1946)(121) Hack (1974)(122) Schmidt (1982)(123) Yates (1984)(124) Roodhooft (1984)(125) Bankier (1985)(126) Humbert (2014)(53) Madison (1934)(127) Kohn (1973)(128) Zonana (1976)(129)
	611279	1q32.1	KIF14 #	AR	BRA, cystic renal dysplasia	Microcephaly, cerebellar and vermis hypoplasia	Prenatal (with postmortem)	Unknown	Filges (2014) (25) Meier 2019 (36)
Cenani-Lenz syndrome	212780	11p11.2	LRP4	AR	BRA, URA, Hypoplasia	Hand and foot malformation, skeletal	Prenatal	Unknown	Li (2010)(58)
Nephronectin dysregulation	610306	4q24	NPNT	AR	BRA, URA, renal dysplasia	Unknown	Prenatal	Unknown	Dai (2022) Al-Hamed (2022)
RET *	164761	10q11.21	RET	AD	BRA, URA, renal hypoplasia	Urogenital, MCKD, Hirschprung, MEN2-associated tumors	Postmortem Postnatal	2:1	Skinner (2008)(31) Hwang (2014)(90) Hibi (2014)(130) (67)
Neurooculorenal syndrome (NORS)	620305	3p12	ROBO1	AR	BRA, URA	Cerebral/pituitary malformation, ocular, facial dysmorphism, urogenital, cardiac malformations, and other CAKUT, developmental delay	Prenatal	Unknown	Calloni (2017) (64) Kruszka (2017) (65) Munch (2022) (66)
SERKAL Syndrome**	611812	1p36.12	WNT4	AR	BRA, URA	Urogenital, cardiothoracic, lung, adrenal, female to male sex reversal	Prenatal	2:1	Mandel (2008)(131) Wu (2017) (132)
Renal agenesis/hypoplasia/dysplasia	602864	17q21.32	WNT9B	AR	BRA, renal hypoplasia, renal dysplasia	Mullerian agenesis	Prenatal	1:1	Lemire 2021 (74)
Heterotaxy, visceral, 1, X-linked	306955	Xq26.3	ZIC3	XLR	BRA, URA	Urogenital , cardiothoracic, skeletal	Prenatal, Postnatal, Post-mortem	1:0	Mikkila (1994)(133) Reutter (2016)(75)

^*RET: Rearranged during Transfection proto-oncogene

^**SERKAL: 46, XX SEx Reversal with dysgenesis of Kidneys, Adrenals and Lungs

^#These 5 genes are thus far reported in BRA only (no reports of URA)

AR autosomal recessive, AD autosomal dominant, XLR X-linked recessive

BRA bilateral renal agenesis

URA unilateral renal agenesis

^†Features of Potter facies, talipes equinovarus, and pulmonmary hypoplasia, common to all fetuses with severe oligohydramnios are not included in the Table.

Table 3.

Syndromes and Associations with Bilateral Renal Agenesis of Unknown Genetic Etiology

Presentation	OMIM	Inheritance Pattern	Renal Phenotype	Other Phenotype	Sex (M:F)	Timing of Diagnosis	Reference
Acro-renal-mandibular syndrome	200980	AR	BRA	Urogenital, brain anomaly, skeletal anomaly	189: 188	Prenatal	Halal (1980)(134) Tobias (2001)(135)
Holzgreve syndrome	236110	AR	BRA, URA	Cardiothoracic, skeletal anomaly	1:0	Postnatal	Thomas (1993)(89) Holzgreve (1984)(88)
Isolated Midline Defect	313850	XLR	BRA	Uncharacterized	1:0	Postmortem	Toriello (1985)(79)
Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) *	277000		BRA, URA	Urogenital, brain anomaly, skeletal anomaly	1: 3	Postnatal	Buchta (1973)(11) Knudsen (1979)(136) Cheroki (2006)(137) Herlin (2014) (138)
Splenogonadal fusion limb defects	183300	Sporadic	BRA	Splenogonadal fusion, limb defects	2.75:1	Prenatal	McPherson 2003(78)
VACTERL association	192350	AD with incomplete penetrance and variable expressivity	BRA, URA	Urogenital, cardiothoracic, skeletal anomaly	2:0	Prenatal, postnatal	Auchterlonie (1982)(139) Castori (2008)(140)

VACTERL: Vertebral defects, Anal atresia, Cardiac malformations, Tracheoesophageal fistula with esophageal atresia, Radial or Renal anomalies and Limb anomalies

AR autosomal recessive, AD autosomal dominant, XLR X-linked recessive

^*GREB1L, WT1, TBX6, SHOX, WNT4, WNT9B, HNF1B, and LHX1 are candidate genes (DeTomasi et al. 2017, Lemire et al. 2021, Sanna-Cherchi et al. 2017; Baffour and Kwarkoh 2021)

Single gene disorder syndromes identified in BRA and not reported in URA

Five disorders and the corresponding five genes responsible have so far been identified in cases of BRA with no reports of URA (Table 2). Of note, it is possible that these genes are capable of causing a URA or alternative renal phenotype that has not yet been discovered or reported. The five genes responsible for these syndromes were BICC1 (12), CEP55 (21), FGF20 (22), GFRA1 (23, 24), and KIF14 (25). Aside from typical findings of Potter facies, talipes equinovarus, and lung hypoplasia, all secondary to oligohydramnios in the absence of kidneys, all but one of these reported disorders have phenotypic features that can aid in diagnosis.

Four of these six disorders are inherited in an autosomal recessive manner; two are autosomal dominant. Renal Hypodysplasia/Aplasia 2 (RHDA2) is the only one of these disorders in which BRA seems to have been reported only as the sole finding without additional prenatal or postnatal phenotypes. RHDA2 is caused by a homozygous mutation in the FGF20 gene (22) associated with isolated BRA or reno-ureteral agenesis. FGF20 represents but one member of the fibroblast growth factor family which, through mitogenic and cell survival activities, exerts control of cell embryonic growth and morphogenesis during development. Murine studies indicate that FGF20 is expressed within nephron progenitors and plays a dominant role in development of the kidney (22).

One case of BRA accompanied by a meningomyelocele has recently been reported in association with de novo heterozygous BICC1 likely pathogenic variant (12). BICC1 is implicated in cystic renal disease in a murine model (26) and in 2012, BICC1 loss of function variants were reported in two children, both male, with cystic renal dysplasia (27). Both were diagnosed prenatally with imaging suggestive of renal dysplasia in one kidney, and in each case the mutation was inherited from an unaffected parent, suggesting incomplete penetrance. Given the single report (12) to date, BICC1 is likely a rare cause of BRA but another good example of the spectrum of phenotypes with which many CAKUT genes, including those involved in ciliary formation and function may present, both prenatally and postnatally.

Homozygosity for variants in CEP55 is usually associated with bilateral renal dysplasia in an autosomal recessive syndrome in which hydranencephaly is a prominent feature. Two early reports of the syndrome, however, are described as having BRA, in neither of which, of note, was CEP55 analysis performed (28, 29). Loss of function in CEP55 is thought to cause impaired cell migration during embryonic development (30).

Biallelic loss-of-function variants of GFRA1, which encodes a family member of the glial cell lines-derived neurotrophic factor proteins, has been reported to lead to what will appear to be isolated BRA on prenatal ultrasound, but also leads to Hirschprung disease (23, 24). As a co-receptor for the tyrosine kinase receptor RET, Gfra1 negative mice have renal agenesis by a similar though not yet fully understood mechanism as in mice lacking the gene for RET. In humans GFRA1 mutations are rare as compared to RET mutations, but they do exist among patients with BRA (23, 24, 31). It is postulated that both GFRA1 and RET loss of function mutations disrupt initial ureteric branching through a loss of RET signaling (24, 31). There is an often underappreciated association between CAKUT and Hirschsprung’s disease, likely mediated by RET signaling (32, 33). RET is a proto-oncogene coding for a tyrosine kinase receptor, whose mutation leads to apoptosis of RET-expressing enteric neuroblasts and likewise regulates cellular proliferation and apoptosis in the ureteric bud, potentially explaining this clinical association (34, 35).

KIF14 encodes a member of kinesin-related ATP-dependent microtubule-based motor proteins that are involved in intracellular transport of membrane-associated organelles, and in proper spindle formation during mitosis. Kif14, like other members of the kinesin family, is crucial for ciliogenesis and for intraflagellar transport. KIF14 variants appear to cause a lethal ciliopathy as a severe fetal phenotype within a spectrum of a viable postnatal phenotype (36). Filges et al. (25) described this lethal fetal condition as the first human phenotype associated with bi-allelic KIF14 mutations. Ciliopathies affect all organ systems, as virtually all vertebrate cell types produce cilia which control cell signaling pathways. The first of two female fetuses in a non-consanguineous couple, had autopsy-confirmed BRA, uterine hypoplasia, microcephaly, and cerebellar hypoplasia with vermian agenesis, along with early severe growth restriction, while the subsequent sibling had similar findings but bilateral renal cystic dysplasia. Both fetuses shared biallelic truncated mutations in KIF14. Interesting and deserving of further study is that the Kif14 knockout mouse model recapitulates the brain anomalies found in human, but not the renal phenotype (25).

Single gene disorders identified in cases with BRA or URA

It is noteworthy that in the identified conditions associated with either URA or BRA, the renal agenesis may sometimes appear isolated on prenatal ultrasound (Table 2). The fifteen conditions, associated with altogether sixteen genes which may present as BRA or URA, with or without contralateral findings, are described as follows.

Kallman syndrome is an X-linked clinically heterogeneous genetic syndrome resulting in hypogonadotropic hypogonadism. When caused by a mutation in ANOS1 (KAL1), fetuses can manifest with BRA or URA (37–39). Of note, the Human Genome Organization (HUGO) has proposed to the scientific community that the nomenclature in regard to this gene be standardized to that of ANOS1 (40).

Antley-Bixler syndrome is characterized by premature closure of the lamdoidal and coronal sutures, proptosis and mi-face depression, bowing and fractures of the femora, tibiae and unale, as well as renal agenesis (BRA or URA) and imperforate anus as reported by Le Heup in 1995 (41). Other genitourinary malformations may include duplicated dysplastic kidneys, hypoplastic vagina or atresia of the lower third of the vagina, duplicated uterus, rectovaginal fistula, and fusion of the labia majora. The gene responsible for both the autosomal recessive and autosomal dominant forms of this syndrome, FGFR2, encodes for one of the highly conserved fibroblast growth factors which play important roles in many developmental processes. For FGFR2 this spans from neuronal formation, migration and survival to osteoprogenitor proliferation, differentiation and apoptosis; early differentiation is thought to underlie premature cranial suture fusion. Hence, Antley-Bixler is one of eight FGFR2-related craniosynostosis syndromes, and is not the only one that may have concomitant genito-urinary associated anomalies (42). The mutations appear to be specific to these eight craniosynostosis syndromes, making FGFR2 a gene of great interest to further study genotype-phenotype relationships: how subtle differences in downstream activities might explain not only why specific cranial sutures are affected, but also how they give rise to any extracranial abnormalities such as BRA or URA in Antley-Bixler syndrome (42).

Fraser Syndrome is an autosomal recessive disorder characterized by cryptophthalmos, ear abnormalities, syndactyly, ambiguous genitalia, intellectual disability, and laryngeal malformations (43–45). Cases of Fraser syndrome with BRA have been observed with a mutation in mainly two genes, FRAS1 or FREM2 (44–46). BRA and URA are common, reported in 38% and 36% of all cases, and BRA with FRAS1 in particular (48% of FRAS1 cases versus 33% of FREM2 cases) (45). Additional findings have included a univentricular heart, polydactyly, anal stenosis/atresia, skull ossification defects, umbilical cord anomalies, and absent vagina (47).

Mutations in EYA1, which codes for a phosphatase controlling cell growth and proliferation, has been implicated in BRA and URA (48–50). Autosomal dominant heterozygous variants in EYA1 are responsible for Branchiootorenal syndrome type 1. Ear malformations including preauricular pits are a prominent feature in individuals with EYA1 variants (48, 49, 51). Additional findings may include hearing loss, structural malformations in the ear, and branchial fistulas or cysts, however, these may not be visualized via prenatal ultrasound.

Renal Hypodysplasia types 1, 2, and 3 have been attributed to ITGA8, FGF20, and GREB1L, respectively. Renal Hypodysplasia/Aplasia 1 (RHDA1) is caused by homozygous or compound heterozygous mutations in ITGA8 (coding for integrin subunit alpha 8, critical in embryonic kidney development) or FGF20 (17, 52, 53). FGF20 we have previously discussed in the section on BRA only and RHD2. Findings for RHDA1 and RHDA2 are generally limited to a spectrum of renal phenotypes and urogenital tract anomalies. GREB1L encodes for a protein likewise critical in tubule development of the kidney, and in Wolffian and Mullerian duct formation. Associated with RDHA3, the most severe type of RDH, a heterozygous loss-of-function or missense variant in GREB1L can cause BRA, and mutations in this gene are also associated with other urogenital as well as skeletal, ear, and sometimes cardiac abnormalities (17, 52, 54).

GLI3-related Pallister-Hall syndrome has a spectrum of abnormalities aside from BRA/URA: postaxial or mesoaxial polydactyly, bifid epiglottis, laryngotracheal cleft, anal atresia or stenosis and hypothalamic hamartoma and pituitary insufficiency. The latter may result in neonatal demise due to undiagnosed adrenal insufficiency. In this autosomal dominant condition, mutations in GLI3 consist of small intragenic deletions or insertions and missense, nonsense, and splice site variants (55). GLI3 encodes a zinc finger transcription factor downstream in the sonic hedgehog pathway. GLI3 transcription then regulates genes further downstream. In Pallister-Hall syndrome the truncated protein product is predicted to act as a constitutive repressor to its downstream targets. Aberrant hedgehog signaling during mammalian embryonic development deters normal organogenesis, inclusive of the kidney (56).

Shortening and fusion of the bones in the upper extremities in addition to syndactyly occurs in autosomal recessive Cenani-Lenz syndrome due to a mutation in the LRP4 gene (57). LPR4 function, required for Wnt signaling, has a central role in both normal limb and normal kidney development, with over 50% of families having pathogenic mutations in LPR4 exhibiting renal agenesis (BRA or URA) or renal hypoplasia (58). Murine LPR4 knockout studies (57) have corroborated bilateral or unilateral renal agenesis.

Neurofacioskeletal syndrome with or without renal agenesis (NFSRA) refers to a distinctive phenotype characterized by facial dysmorphism (coarse facies, upslanting palpebral fissures, broad nasal tip and wide mouth), developmental delay, intellectual disability, agenesis or hypoplasia of the corpus callosum, limb contractures, bradydactyly, and broad tips of the digits, along with unilateral or bilateral renal agenesis (59). This autosomal recessive disorder is attributable to defective heparan sulfate synthesis from biallelic pathogenic variants in HS2ST1, and in turn defective signaling from molecules such as those of the fibroblast growth factor family which require heparan sulfate in order to work. Knockout mice show bilateral renal agenesis and skeletal malformations (60).

Dai et al. described a consanguineous Han family in which 3 siblings exhibited prenatally diagnosed BRA in which a pathologic homozygous frameshift variant with NPNT was found, leading to a premature stop codon (61). A knock-in murine model homozygous for the same mutation replicated the BRA phenotype. Subsequently, Al-Hamed et al. reported a consanguineous couple in which BRA presented in siblings in whom a homozygous null founder variant in NPNT was detected (62). NPNT encodes for nephronectin, which appears to regulate GDNF expression that is essential in the metanephric mesenchyme to promote ureteric bud invasion thereof. While biallelic NPNT mutations may also present with cystic renal dysplasia, the recent clinical cases reported above are the first to be described with renal agenesis (62, 63).

In support of a role for ROBO1 in axonal guidance, syndromes with biallelic pathogenic variants in this gene initially focused on cerebral and neurodevelopmental abnormalities (64). The role of ROBO1 in nephrogenesis, in the metanephric mesenchyme, involves renal tubular development. The effects in ROBO1 mutant murine models appear much more pronounced in the collecting ducts, with severe cystic dilation thereof, than in the proximal renal tubules. Characterized clinically by markedly variable expressivity and intrafamilial variability, biallelic ROBO1 mutations, similar to ciliopathies, lead to not only URA and BRA but also other renal and (in females) uterine anomalies plus extra-renal abnormalities: cerebral, pituitary, and ocular abnormalities, cardiac abnormalities, and neurodevelopmental delay (65, 66).

RET encodes for the GDNF receptor which, as mentioned earlier, has a central role in growth and branching of the ureteric bud in early renal development as the mammalian kidney forms via reciprocal induction between the ureteric bud and the metanephric mesenchyme (1, 31, 67). Loss of function mutations in RET have been reported in individuals with CAKUT inclusive of BRA and URA, as well as Hirschsprung disease (68, 69). A study of 29 stillbirth fetuses with renal agenesis identified a heterozygous RET mutation in 7/19 (37%) of those with BRA and in 2/10 (20%) of those with URA (31), ranking RET among the most frequent genes reported in BRA. RET is also a protooncogene associated, through gain of function mutations, with several cancer related syndromes, e.g. multiple endocrine neoplasia type 2 (characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia or adenoma), in addition to URA/BRA or severe renal dysplasia (31, 69–72).

A mutation in the WNT4 gene can cause SERKAL (Sex Reversion, Kidneys, Adrenal, and Lung dysgenesis) syndrome or Mullerian aplasia and hyperandrogenism, both of which are characterized by urogenital abnormalities including sex reversal (female to male) and abnormalities of the kidneys or adrenal glands (73).

Biallelic homozygous mutations in WNT9B in two unrelated consanguineous families have been reported in siblings having either renal hypoplasia, renal dysplasia, or BRA (74). The clinical phenotypes associated with WNT9B mutations, which have been recapitulated in a murine model, also include that of Mullerian agenesis in females who are heterozygous for mutations in WNT9B making it also one of several candidate genes for Mayer-Rokitansky-Kuster-Hauer syndrome (see footnote of Table 3).

Finally, ZIC3 encodes a zinc finger transcription factor involved in laterality and situs. Mutations of this gene are responsible for Heterotaxy Visceral 1, X-linked (HTX1) (9, 75).

Some syndromic conditions may present as isolated BRA on prenatal ultrasound. Kallman syndrome, for example, may present as isolated BRA on prenatal ultrasound. Other phenotypic features of the listed single gene disorders may be missed during prenatal ultrasonography particularly in the setting of oligohydramnios, thus giving the prenatal impression of isolated BRA.

Clinically recognized syndromes of unknown genetic etiology

Out of multiple syndromes, associations, and field defects that are likely to, or that at least that have been proposed to have, potentially, a cytogenetic or single gene etiology that may present with renal agenesis, six include cases with BRA (Table 3). More specifically, 3 of these have presented with BRA and 3 both URA and BRA.

Acrorenal-mandibular syndrome (autosomal recessive) (76, 77), Splenogonadal fusion limb defects syndrome (78) and X-linked familial Isolated Midline Defects syndrome (79) are reported with BRA only. The accompanying limb defects may not always be obvious on prenatal ultrasound due to anhydramnios. Whereas two of these may be able to be differentiated based on inheritance pattern, Splenogonadal fusion (wherein the spleen is connected to the gonads) is sporadic, is associated with severe limb deficiencies in about 20% of cases reported, and is rarely accompanied by BRA (78, 80). Splenogonadal fusion limb defect “syndrome” may represent a field defect or a vascular disruptive event early in the first trimester, but a genetic etiology may underly some cases (80). The evidence for this, however, is limited to one case born to consanguineous parents (81) and one case of Roberts syndrome with premature centromere separation (82).

The VACTERL association (vertebral defects, anal atresia, cardiac defects, trachea-esophageal fistula, radial or renal anomalies, and limb abnormalities), Holzgreve syndrome, and Mayer-Rokitansky-Küster- Hauser (MRKH) syndrome have been documented in cases of both URA and BRA (Table 3). Multiple candidate genes have been proposed for MRKH, including GREB1L, WT1, TBX6, SHOX, WNT4, HNF1B, and LHX1 (83). For example, a report of a single missense mutation in TCF2 also known as HNF1B in a patient with VACTERL having a unilateral multicystic dysplastic kidney, anal atresia, a ventricular septal defect, and a tracheal-esophageal fistula, suggests this as one possible candidate gene (84). Interestingly, the same mutation in HNF1B/ TCF2 was also reported in an adult with URA (85). Variants in the HNF1B/ TCF2 gene, however, have not been reported to our knowledge in fetuses with BRA (86). Nor has 17q12 deletion syndrome, which is likely, at least in part, driven at least in part by the loss of HNF1B (87).

Holzgreve syndrome (88), also known as Thomas syndrome (89), thought to be autosomal recessive, presents with multiple congenital anomalies: BRA (or renal hypoplasia), bilateral cleft lip and palate, and complex heart defects. The molecular genetic basis is not understood. Again, our review excluded many additional (N=16) syndromes which had reported no cases of BRA but rather only URA. As was the case for the vast majority in the single gene disorders category, it is worth noting that all of the entities in Table 3 have additional features in addition to BRA.

Timing of and Difficulties Encountered in Diagnosis

Clearly, BRA presents with prenatally diagnosable findings including oligohydramnios and absent kidneys, and the timing of diagnosis in the published reports was based primarily on study design. BRA reported in a postnatally ascertained case report certainly does not preclude its potential to be detected prenatally. Nor, conversely, are we able to conclude, based on the studies reviewed, how often renal agenesis is misdiagnosed on prenatal ultrasound. Fetal MRI which, compared to ultrasonography, does not depend on amniotic fluid for visualization and is less hampered by maternal habitus and fetal position, can be useful in the setting of oligohydramnios, ruling out ectopic kidney versus renal agenesis, and in the evaluation of extrarenal anomalies, intracranial in particular. The ability to accurately diagnose BRA prenatally is important for accurate prognostic and recurrence risk counseling. In our literature review of BRA, multiple authors documented having made a prenatal diagnosis via ultrasound imaging and 12 authors documented originally a post-mortem diagnosis via autopsy. The information provided in the latter set of articles likewise does not allow for a clear assessment of how frequently these findings are misclassified on prenatal ultrasound.

Sex

Renal agenesis has been reported to be more prevalent in males than females (8), although a more recent autopsy series of 10 cases of BRA yielded a male:female ratio of 1:1 (9). Our research yielded male to female ratios for both unilateral and bilateral renal agenesis to be approximately 2:1. We noted 3 of the identified 22 non-chromosomal disorders to be X-linked; this would appear to provide only a partial explanation for the male preponderance.

Laboratories and Available Genetic Testing

Utilizinggenetests.org and searching commonly utilized genetic laboratories for the BRA and URA genes, we identified many United States laboratories that offer testing. Sequencing of many genes are offered as part of a CAKUT panel, however individual gene sequencing is also occasionally available. Genes responsible for renal agenesis may also be found in skeletal dysplasia panels or onco-gene panels. Turn-around time may be important in prenatally diagnosed cases, and while whole exome sequencing or whole genome sequencing may be the more optimal and most comprehensive molecular method, panel tests can provide more timely results. As no CAKUT gene panel comprised all of the single genes we have identified herein, a custom “slice” panel would be necessary to accommodate all 20 of them. As new genes responsible for BRA are still being identified, moreover, whole exome sequencing would seem a worthwhile approach today, particularly for isolated BRA on prenatal ultrasound.

Discussion

This review presents a comprehensive summary listing of known genetic etiologies of BRA. We identified 6 cytogenetic abnormalities and 21 genes associated with BRA and reviewed their concomitant findings. These genes provide clues to the mechanisms leading to BRA which are gradually being elucidated. Figure 1 illustrates the interconnected pathways of known genes and genetic products involved in the pathogenesis of BRA. Differing genes’ expression in the mesonephros and metanephros that may lead to cessation of renal development further accentuates the fascinating complexity inherent in normal renal embryonic development, which is an area of active and prolific investigation. We also reviewed clinically recognized syndromes and associations for which renal agenesis is a component and for which there is no known underlying genetic etiology, identifying 6 which have presented with BRA. In documenting associated anomalies for each confirmed diagnosis of a syndrome or disorder, our study also demonstrates the plethora of associated organ system findings.

Figure 1.

Known genes and cellular pathways involved in bilateral renal agenesis. Shown is a diagram of a cell demonstrating the different cell surface receptors, intracellular signaling partners, and nuclear elements known to be involved in the pathogenesis of BRA. ECM: extracellular matrix. (Original artwork by GWK).

Seven studies (12, 13, 17, 19, 54, 90, 91) employing gene sequencing in large series of CAKUT have been seminal to our review. Out of a total of over 75 CAKUT-related genes from these studies, however, only 10 genes cited in these CAKUT case series have been implicated specifically in BRA, and only De Tomasi (17), Sanna-Cherchi (18), and Jordan (12) include BRA in their published study populations. Most of these large case series entailed postnatal investigation of patients often referred from pediatric nephrologists as opposed to fetuses who, with BRA, would not have survived postnatally. Thus, only these three, De Tomasi et al in particular which focused on BRA, were able to be directly contributory to the objective of the current study, and necessitated for our study a full literature search to be conducted as described to thoroughly ascertain single genes associated with BRA. Our study’s extensive literature review identified 11 more genes from other published reports, as either single case reports or small case series.

Genetic causes of URA are outside the scope of this review. In addition to the conditions cited herein, amongst the array of genetic disorders that have been reported in association with URA, are Alagille syndrome, Diamond-Blackfan anemia, Duane-Radial ray syndrome, Fanconi anemia, renal hypodysplasia, Tetra-amelia syndrome, tumor necrosis factor receptor mutation, Townes-Brock syndrome, and Waardenburg syndrome. Some of these might, in the future, be reported to have BRA as a phenotype (92–99). These are all multisystemic disorders that involve diverse organ systems including the hematological, musculoskeletal, ocular, neurological, and gastrointestinal systems, in addition to the genitourinary system. Thus, genes fundamental to early development and pertinent to multiple organ systems, including the renal system, tend to be involved.

It is understandable why the terminology “congenital anomalies of the renal and urinary tract” (CAKUT) is often utilized. In performing this literature review it was affirmed that renal anomalies among cases with identical gene mutations, even those within the same family, tend to have a heterogeneous and variable presentation. It was also evident that variants in genes that cause other renal phenotypes can also result in renal agenesis. The findings of other associated renal malformations, such as a multicystic kidney, can yield clues that can help to elucidate the underlying pathomolecular processes of congenital genitourinary anomalies (17, 100). The pathology may vary by genetic etiology and involve a malformation secondary to improper protein signaling, or a renal anomaly that occurs secondary to an obstructive uropathy. We did not include in our review genes that appeared to uniquely cause renal hypoplasia, cystic or multicystic kidney disease in the absence of renal agenesis, yet we acknowledge that renal agenesis may be reported in association with these genes in the future.

We do not know whether or not the cases in Table 3 identified as being of an unknown genetic etiology may actually be variable manifestations of currently known genes or if they involve novel genes yet to be identified. Some of the entities in Table 3 may not be attributable to a singular genetic cause. Furthermore, it is possible that a phenotype of renal agenesis was mistakenly documented when the true phenotype was actually renal hypoplasia, therefore implicating causation of a gene that does not truly cause primary renal agenesis, as renal hypoplasia and renal agenesis may often be clinically indistinguishable on prenatal ultrasonography.

Unsurprisingly, we found that the majority of genes were identified and reported after 1995. Due to the routine use of prenatal ultrasound combined with advances in imaging technology over the past 3 decades, renal agenesis is nowadays often detected prenatally. On detailed examination, the fetal kidneys can be visualized ultrasonographically by approximately 12 weeks gestation, while normal amniotic fluid is maternally derived until approximately 16-18 weeks’ gestation (101). Thus, oligohydramnios and anhydramnios secondary to BRA are not expected to occur until after 18 weeks’ gestation. In line with the enhancements in and more widespread usage of obstetrical sonography, we found that the majority of cases of BRA after 1995 reported a prenatal diagnosis while the majority of the cases before the year 1995 were diagnosed in the postnatal period or at autopsy. The importance of fetal autopsy, however, should not be overlooked in light of the inherent difficulties of making an accurate diagnosis of renal agenesis versus other renal abnormalities by prenatal ultrasound in the setting of severe oligohydramnios or anhydramnios. Indeed, the oligo/anhydramnios that accompanies renal agenesis can make prenatal anatomical survey challenging, as accurate ultrasound imaging requires the anechoic amniotic fluid to act as a window.

In the era of next generation sequencing, additional single gene variants are continually emerging. The full phenotypic spectra associated with variants in the genes that are reported have yet to be clarified. When fetal cases are included in future genetic invesigations of CAKUT, BRA will predictably be evaluated more often, as illustrated by a large series published in 2022 of 100 fetuses with severe renal defects was examined by targeted next-generation sequencing, of which 8 cases had BRA (12). The phenotypic overlap between BRA and other renal presentations is exemplified by cases such as their BRA case with a pathogenic variant in BICC1, which previously had only been associated with cystic forms of renal dysplasia (12).

A likely inheritance pattern may aid establishing a genetic diagnosis. Autosomal dominant, autosomal recessive and X-linked syndromes may be suggested through a family pedigree. For example, in this current review, 2 genes and one syndrome of unknown etiology were identified as X-linked; as such, suggestion of X-linked transmission will narrow the differential diagnosis.

The association of both BRA and URA with multi-organ system syndromes emphasizes the need for a detailed fetal anatomy ultrasound for prenatally diagnosed renal agenesis. For livebirths pediatric genetics consultation is likewise important postnatally along with neonatal imaging, and postmortum, a careful pathologic examination. Though, prenatally, renal agenesis may initially appear isolated on sonographic imaging, identification of additional findings may be crucial to management and establishing a genetic diagnosis.

Several gene panels currently exist that test for genes associated with CAKUT. Other genes not included on CAKUT panels may be found on skeletal dysplasia panels. Depending on the sonographic and other antenatal clues presenting to the fetal dysmorphologist, whole exome slice panels may also be constructed to approach the diagnosis. That being said, and given the likely expanding recognition of genetic etiologies for BRA (25), a more comprehensive approach to the diagnostic workup lies in performing whole exome and whole genome sequencing.

This review has several limitations. Every effort was made to present accurate data as reflected in the current English language literature; however we acknowledge challenges due to the spectrum of renal presentations. Limiting the study to English language published papers means that additional reported genetic etiologies for BRA may have been missed. We present this review as a useful adjunct to establishing a specific diagnosis in a fetus or newborn with BRA. Though yet unproven, it does seem plausible that renal agenesis can be the unique result of a certain category of specific gene variants; however, the genes we found to be associated with only BRA and not only renal phenotypes may well be found to have an expanded renal phenotype in the future. Likewise, due to variable expressivity and incomplete penetrance, the phenotypic spectrum of variants in the identified genes herein will surely require updates as more genetic studies are published. The practitioner diagnosing BRA, either on prenatal ultrasound or on postmortem examination, may not know if a mutation is de novo or inherited from an affected parent who may have URA since some genes can cause both. This highlights the importance of investigating a potentially molecular cause of renal anomalies. Finally, the present article uses OMIM terms for categorizing renal and extrarenal phenotypes, however it should be noted that there is a movement away from this and towards perinatal Human Phenotype Ontology (HPO) terms per a recent consortium of perinatal genetics experts, organizing them according to groups such as musculoskeletal anomalies, neurology, hydrops fetalis, craniofacial malformation, cardiology, and placental pathology (102). Moving forward, we acknowledge that such terminology will likely come to supersede the previous system.

In summary, clinicians encountering the finding of BRA should be mindful of the array of additional findings associated with BRA. Whether in the future there will be single gene disorders associated with truly isolated BRA, by careful phenotyping of case series, postmortem examination, and by contributory phenotypic findings in other family members having the same deleterious gene, remains to be determined. Multiple genes have been implicated in URA and BRA that may also present with other CAKUT findings. Many extrarenal manifestations of renal agenesis, furthermore, such as developmental delay, may not present until well after birth, and should thus be considered in counseling parents facing a new prenatal diagnosis of renal agenesis. Parental counseling will initially depend upon whether the fetus appears to have isolated renal agenesis or a clinically recognized syndrome for which there may be a yet unidentified genetic etiology. Clinicians today recognize the expectation for there to be additional genes in the future implicated in BRA along with the complexity that variable expressivity engenders. Counseling parents in the setting of BRA, as is true of other forms of CAKUT, is expected to be informed increasingly by fetal genetic testing. Comprehensive counseling becomes especially relevant given technological advances in Medicine that may improve short- and long-term survival outcomes for those afflicted with BRA (5). We hope that the tabulated data herein will serve to assist perinatal teams in their counseling and in initiating the workup towards achieving an exact diagnosis.