Exploring Familial Hypospadias: Genetic Insights from Copy Number Variants in a Quad Family

doi:10.21203/rs.3.rs-4843906/v1

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Exploring Familial Hypospadias: Genetic Insights from Copy Number Variants in a Quad Family

https://doi.org/10.21203/rs.3.rs-4843906/v1

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The genetic aetiology of hypospadias is likely to be oligogenic with possible interactions between multiple genetic variants and contributory environmental factors. A pathogenic copy number variant (CNV) is usually harboured by 3–14% of patients with rare developmental disorders. With this background, a landscape of CNVs in a family with multiple affected and unaffected progeny is presented with an investigation into the potentially responsible, molecular pathways underlying the etiopathogenesis of hypospadias. The family consists of both parents, two sons with hypospadias, and two unaffected sons (whole exome data unavailable for one unaffected son). CNVkit pipeline was executed and the structural variant files were annotated. The identified CNVs were studied for distribution within the family, inheritance, gene-composition and correlated with available information for potential relevance to the phenotype.

Cumulative analysis (F:father, M:mother, P1-P2:affected progeny, U:unaffected progeny) identified 152 unique CNVs[size:1.49 kb–6.53 Mb) comprising 139 deletions and 13 duplications. P1 & P2 have been represented by 29(of 52) & 22(of 50) de novo CNVs respectively. P1 & P2 have 16 common deletion CNVs:8/16 CNVs are absent in U (inherited:6, de novo:2); de novo CNVs: chr6:29100942:29306930:DEL & chr16:11379821:11441076:D. de novo CNVs encompass OR2J1 and OR14J1 genes expressed in testis and spermatozoa as major histocompatibility complex (MHC)-linked olfactory receptors. CNVs encompassing GREM1, RRN3, KIAA0753 and HNF1B genes relevant to hypospadias were identified.

The landscape of CNVs in familial hypospadias has been presented to enhance the understanding of their distribution, frequency and impact on the development of hypospadias and a database has been generated for future research.

hypospadias

whole exome sequencing

copy number variants

single nucleotide polymorphisms

OR2J1

OR14J1

GREM1

HNF1B

KIAA0753

RRN3

The etiopathogenesis of hypospadias has been ascribed to genetic composition, endocrine disruptors, maternal factors and aberrations during embryonic development. It is known to have a genetic component with reported heritability of 56.9%[1]. Familial clustering has been described with recurrence in 17% (1 in 6) siblings. Although specific genetic mutations or chromosomal abnormalities have been identified and reported in hypospadias, definitive genes and mutations are largely elusive.

Traditionally, whole exome sequencing (WES) data analysis primarily focuses on single nucleotide polymorphisms (SNPs) WES-based calling, however offers superior sensitivity for pathogenic CNVs[2]. A pathogenic CNV is usually harboured by 3–14% of patients with rare developmental disorders; they might have a crucial role in hypospadias etiopathogenesis, particularly in familial cases or instances wherein traditional single-gene mutations do not fill the gaps in understanding the genetic architecture. Beleza-Meireles et al[3] identified significant enrichment of rare CNVs in patients with hypospadias. Kaminsky et al[4] demonstrated a higher burden of both rare and common CNVs in individuals with developmental disorders, including hypospadias. Chen[5] and van der Zanden[6] have identified CNVs in independent cohorts of hypospadias patients through WES and high-resolution SNP arrays respectively. Familial cases offer a unique opportunity to investigate the inherited CNVs providing insights into the etiopathogenesis and lead to novel pathogenic mechanisms and potential therapeutic targets.

The current synthesis has analysed and presented a landscape of the copy number variants in five family members two of whom are affected with hypospadias, to identify potential molecular etiopathogenetic pathways responsible for the disease.

The whole exome data pertains to five (of six) members in a hypospadias family (F: father, M: mother, P1 & P2: two siblings with hypospadias respectively, U: unaffected sibling; another unaffected sibling in the family was not subjected to WES) was downloaded from the European Nucleotide Archive[7] (Project: PRJNA982072; SRR24882981-85)[Supplementary Fig. 1].

The CNVkit pipeline was executed on the recalibrated BAM files and CNV calling was performed using the CNVkit toolkit [8]. CNVs encompassing genes related to hypospadias were prioritized and visualized using chromosome ideograms. The CNVs were annotated (Annotsv tool) to add ACMG classification, breakpoints annotations, gnomAD, ClinVar, ClinGen, dbVar and regulatory elements annotations.

Literature search was conducted to determine the potential role of short-listed genes in the etiopathogenesis of hypospadias and identify the possible underlying pathways.

Landscaping of CNVs in the members of the family: Cumulative analysis across the five samples in the study cohort revealed the presence of 152 unique CNVs (size: 1.49 kB–6.53 Mb, median: 206 kb, IQR: 784.24 kb) [Figure 1] comprising 139 deletions and 13 duplications (Supplementary Table 1).

Parents

The father and mother have been represented by 51 (48 deletions & 3 duplications) CNVs and 37 (all deletions) CNVs; 16 CNVs are shared between the two (consanguineous marriage). Seven of these common (16) CNVs have been transferred to all three siblings including two with hypospadias (P1&P2), 4 CNVs have been transferred to affected progeny only (P1 & P2) and 2 CNVs have been transferred to neither. None of the common CNV has been transferred exclusively to the unaffected progeny.

P1 (Affected sibling)

Represented by 52 CNVs (49 deletions & 3 duplications). Twenty CNVs have been inherited from one or both parents; 5, 2 and 13 from the father (only), mother (only) and both respectively; all the inherited CNVs were deletions[Supplementary Fig. 2a].

P2 (Affected sibling)

Represented by 50 CNVs (47 deletions & 3 duplications). Twenty-six CNVs have been inherited from one or both parents; 10 (of which 2 are duplications), 4 (all deletions) & 12 (all deletions) CNVs have been inherited from the father (only), mother (only) and both respectively[Supplementary Fig. 2b].

U (Unaffected sibling)

Represented by 45 CNVs (43 deletions & 2 duplications). Eighteen CNVs have been inherited from one or both parents; 5, 4 and 9 have been inherited from the father(only), mother (only) and both respectively; all the inherited CNVs are deletions.

CNVs common to the two affected siblings and not present in the unaffected sibling

P1 & P2 have 16 CNVs in common; all deletions. Of these 8 CNVs are not present in the unaffected sibling and considered highly relevant in context[Table 1].

De-novo CNVs found in the progeny

There were 29 (26 deletions, 3 duplications), 22 (21 deletions, 1 duplication) and 26 (24 deletions, 2 duplications) de novo CNVs (not inherited from the parents) in P1, P2 and U respectively.

The de novo CNVs present in P1-P2 and absent in U included chr6:29100942:29306930:DEL (genes: OR2J1, OR2J3, OR2J2, LOC124901297, LINC03003, LOC105375006, LOC105375005, OR14J1) and chr16:11379821:11441076:DEL (genes: LOC105371082, LOC400499)[Table 1].

Pathogenicity of the CNVs: Clinical classification (ACMG) identified 21 (of 52) pathogenic CNVs in P1 and 17 (of 50) pathogenic CNVs in P2. Furthermore, 24 and 27 CNVs in P1 and P2 were classified as variants of uncertain significance (VUS)[Supplementary Table 2]. The pathogenic CNVs (n = 55; median: 1.37 Mb, IQR: 1.98 Mb) were much larger than benign CNVs (n = 16; median: 52.13 kb, IQR: 30.60 kb, p < 0.001) and those with uncertain significance (n = 77, median: 84.08 kb, IQR: 222.01 kb, p < 0.001) in the study cohort.

Genes involved with the CNVs

The pathogenic CNVs in P1 & P2 encompass a total of 962 and 884 genes respectively of which there are 475 and 423 protein-coding genes respectively[Supplementary Table 2]. The genes involved with the CNVs identified in P1 & P2 and absent in U were identified and enlisted (Table 1). The genes involved with the CNVs shared between the parents and the hypospadiac progeny (F + M + P1 + P2) and relevant to the etiopathogenesis of hypospadias were identified and explored for respective function (Table 2).

Chromosomal Localization of pathogenic CNVs

The pathogenic CNVs were preferentially mapped to chromosomes 6 and 17 in both P1 & P2 (42.8% in P1 and 35.3% in P2) (Supplementary Figs. 2a&b).

Potential role of CNVs in the etiopathogenesis of Hypospadias: A CNV in P2 viz., chr15:27871862:32969222:DEL (chromosome 15, deletion, q13.1-q13.3) was crossreferenced with a CNV, previously reported in context of ‘hypospadias’[9]. This CNV encompasses 95 genes (Supplementary Table 1) of which GREM1 (Gremlin 1, DAN Family BMP Antagonist; 15q13.3) has been previously implicated in the etiopathogenesis of hypospadias[10]. No abnormalities of the GREM1 gene was detected in other family members.

Further analysis identified 10 and 9 CNVs in P1 and P2 respectively encompassing genes implicated in hypospadias [11–14] (Supplementary Table 3). Within the eight CNVs common to P1 & P2 and not present in the unaffected sibling (U), two specific loci of deletions, viz., chr16:14446887:16294299:DEL (present in F, P1, P2; size: 1.8 Mb; chromosome 16, p13.13) and chr17:6636779:6640043:DEL (present in F, M, P1, P2; size: 3.3kb; chromosome 17, p13.1) relating to hypospadias genes RRN3 (RNA Polymerase I Transcription Factor) and KIAA0753 respectively were identified. While a single copy of RRN3 was deleted as part of CNV in P1, the other copy was mutated at position 21800714 (GRCh38)[NC_000016.10:21800713:A:T; rs556085497; A > T; functional consequence: non-coding transcript variant]. The deletion of KIA0753 was observed across both the alleles.

Annotations revealed that CNV deletions chr17:35764425:38850214:DEL (size: 3 Mb, chromosome 17, q12)[P1, M and U] and chr17:36454631:37925499:DEL (size: 1.47 Mb, chromosome 17, q12)[P2] overlap with genomic regions implicated in congenital anomalies of the kidney and urinary tract (CAKUT). The genes encompassed by these CNVs (Table 3) include those associated with loss-of-function implications in various phenotypes, including developmental anomalies of the kidneys and the urinary tract, renal cell carcinoma, PEHO syndrome[11] and Turnpenny-Fry syndrome[11]. Included amongst these is the HNF1B (Hepatocyte Nuclear Factor 1B/ HNF1 Homeobox B) gene, which is involved in hypospadias[15], CAKUT and RCAD (OMIM 137920) syndrome[16].

Almaramhy et al.[17] have reported a novel, missense mutation involving the HSD3B2 gene (Chr1:119964631T > A, c.507T > A, p. N169K) in all six members of the index family; the SNP was homozygous in the affected members while the parents and the unaffected siblings were heterozygous carriers. Consanguineous marriages offer unique opportunities for genetic studies due to the concentration of genetic variations within the families, particularly those with recessive inheritance. The higher frequency of encountering rare alleles in a homozygous state facilitates the identification of mutations underlying the disease.

The current study identified 152 unique CNVs in a family with two affected siblings, highlighting the potential role of these variants in the development of hypospadias. Both inherited and de novo CNVs have been identified, some potentially relevant to hypospadias in a familial setting. Inherited CNVs are usually more prevalent than the de novo ones and contribute to genetic diversity within families and populations. While the deleterious CNVs are eliminated through natural selection, those that are compatible with life may be concentrated in specific populations due to genetic drifts, population bottlenecks and founder effects, historical migrations and geographical isolation. It is usually the de novo CNVs that play a significant role in developmental or genetic malformations. De novo CNVs may arise during gametogenesis or early embryonic development and are present in most of the cells of the organism. Post-zygotic mutations affecting the germ cells in the parental gonad (gonadal mosaicism) may lead to genetically distinct populations of cells in the gonad of an individual[18]. In such situations, a proportion of germ cells may harbour the damaging CNV which is not necessarily transmitted to all progeny. The same family may have siblings with and without the CNV or more than one sibling sharing the so-called de novo CNVs.

The index family presented with a myriad of CNVs including deletions and duplications. Although both types may be associated with developmental delays, intellectual disabilities and congenital anomalies, the deletion CNVs are usually associated with milder traits to severe developmental disorders depending upon their size and location. Contrarily, duplication CNVs present with altered gene dosages leading to gene over-expression, disrupted gene regulation or novel fusion gene formation.

The presence of three siblings (with WES data) in a family of which two have the hypospadiac phenotype offered a unique opportunity to look into the CNVs potentially relevant to the etiopathogenesis of hypospadias. There were 16 CNVs common to both the affected siblings (P1 & P2) of which 8 were shared with the unaffected sibling. The other CNVs may also be relevant in view of oligogenic or polygenic origin of hypospadias.

Two de novo CNVs, viz., chr6:29100942:29306930:DEL and chr16:11379821:11441076:DEL have been identified in both P1 & P2 suggesting that these new genetic changes may play a crucial role in the etiology of the disease. These CNVs encompass the genes OR2J1, OR2J2, OR2J3, OR14J1, LOC400499, LOC105371082, LOC105375005, LOC105375006, LOC124901297 and LINC03003. OR2J1 and OR14J1 belong to the large olfactory receptor gene family; they are expressed in the testis and spermatozoa as major histocompatibility complex-linked olfactory receptors[19]. Their presence may be indicative of a potential novel mechanism in the development of hypospadias including abnormalities in olfactory receptor expression or signalling pathways during embryonic development. OR2J1, OR14J1 and additional 91 olfactory genes together amount to the specific chemoreceptor repertoire contributing to chemotaxis and chemokinesis; their presence in hypospadias suggest additional functions in reproductive tissues. OR2J1 and LINC03003 genes have been reported previously in context of sexual dimorphism[20], while LINC03003, OR2J2, OR2J3 and OR14J1 have been reported in context of inguinal hernia[21] and LOC105375005 in context of endometrial carcinoma[22].

The pathogenic CNVs have a predilection for chromosomes 6 and 17. Although not directly related to these CNVs, the genes prominently implicated in the etiopathogenesis of hypospadias and located on chromosome 6 include the androgen receptor gene (6q21-q22), steroid 5-alpha reductase 2 gene and HOXA13 genes. The SRXX2 (XX Sex Reversal 2) gene is located on chromosome 17. The CNVs of uncertain significance (VUS) identified in the current analysis have been enlisted warranting further investigation into their potential pathogenicity and contribution to the disease phenotype. Such CNVs are always intriguing for clinicians and patients in terms of risk assessment, management, and genetic counselling.

The analysis identified that the pathogenic CNVs and those with uncertain significance were much larger than the benign CNVs. The finding is congruent with standard knowledge since larger CNVs are likely to involve a larger number of genes including the regulatory regions, adversely affecting critical cellular functions. Simultaneous loss of multiple genes affecting common or related pathways is further relevant in oligogenic and polygenic disorders like hypospadias. The smaller CNVs are not necessarily benign; those affecting single genes may be highly pathogenic too if the gene is indispensable for normal development and function.

The protein-coding GREM1 gene is a part of the DAN family of the bone morphogenetic protein (BMP) antagonist family. It is known to play a role in cell differentiation, proliferation and apoptosis during embryonic development, affecting organogenesis, body patterning and tissue differentiation. The functional implications of this gene relate to the renal and central nervous system development[23]. The gremlin protein relays the sonic hedgehog (SHH) signal from the polarizing region to the apical ectodermal ridge[24]. SHH is involved in the growth and differentiation of the genital tubercle and may be relevant for the development of external genitalia including the penis. GREM1 may also affect the development of urethra and external genitalia through disruption in BMP signalling. Polymorphisms in the GREM1 gene have been linked to increased risk of hypospadias in European and Southern Han Chinese populations[10]. It has also been implicated in the formation and development of the other parts of the urogenital system.

Two CNVs, viz., chr16:14446887:16294299:DEL and chr17:6636779:6640043:DEL directly disrupting the RRN3 and KIAA0753 genes respectively were identified in the affected individuals but absent in the unaffected sibling, strengthening their association with the disease. The RRN3 (RNA Polymerase I Transcription Factor/ Transcription Initiation Factor IA/ TIF-IA) is a protein-coding gene that plays a crucial role in ribosomal RNA transcription[25]; its disruption has been implicated in sexual dimorphism[20], Treacher Collins Syndrome I with under-developed external genitalia[26] and Diamond-Blackfan anemia[26]. The presence of CNVs in RRN3 in the affected siblings but not in the unaffected sibling strengthens its potential role in hypospadias. Renal abnormalities and hypospadias have been reported in individuals affected with Diamond-Blackfan anaemia[27]. The protein-coding KIAA0753 gene is a component of the origin recognition complex (ORC), essential for DNA replication initiation and cell cycle regulation processes critical to genitourinary system formation. The encoded protein regulates ciliogenesis, cilia maintenance and centripolar duplication. Mutations in this gene have been associated with skeletal ciliopathies, autosomal recessive orofaciodigital syndrome XV[60] and autosomal recessive Joubert syndrome 38[28]. The gene has also been associated with hypospadias[29–30] and sexual dimorphism[20].

The HNF1B gene encodes the transcription factor 1B which is relevant to the embryological development of several tissues including the kidneys. Congenital anomalies of the kidney and urinary tract including bilateral cystic dysplasia, structural anomalies of the genitalia, and cysts of the seminal vesicles or the epididymis have been described in affected individuals.

Both the parents and the unaffected sibling did not manifest the hypospadias phenotype despite potentially carrying some of the identified genetic variants (KIAA0753, GGT6, USP6, DPH1 in chr17:108342:6635103:DEL and KIAA0753 in chr17:6636779:6640043:DEL). This observation supports the oligogenic and polygenic theory of inheritance; multiple genetic variants interact in a complex manner and contribute to the disease phenotype, role of incomplete penetrance, the presence of genetic modifiers that modulate disease manifestation. This notion is further reinforced by the observation that the pathogenic CNVs were significantly larger than the benign CNVs, indicating that larger CNVs affecting multiple genes are more likely to be deleterious. The responsible genetic variants present in the affected individuals may work in unison towards hypospadias development through complete disruption of the underlying molecular pathways responsible. Identification of CNVs of uncertain significance (VUS) highlight the challenges in interpreting the clinical significance of CNVs and the need for comprehensive functional studies to elucidate their roles in disease development.

While the analysis is limited to datasets pertaining to a single family, it has successfully created a comprehensive database of CNVs and respective genes potentially relevant to the etiopathogenesis of the condition. Studying CNVs in a single family can uncover rare variants that may not be easily detectable in larger population studies and provide unique insights. The availability of a detailed phenotype, particularly the anatomic differences between the two involved brothers, shall assist in correlating the phenotypic differences with the differentially expressed CNVs between the two affected brothers. The study can serve as a starting point to uncover similar CNV patterns in other affected families and validate these findings through their impact on gene expression or protein function thereby unlocking crucial insights and driving our understanding on genetic basis of hypospadias further. Last but not the least, while CNVs and SNPs may contribute to the genetic architecture of congenital malformations, a comprehensive understanding of either is an indispensable step towards genetic counselling, risk assessment and personalized medicine or potentially targeted therapies.

The present study has presented a landscape of CNVs in hypospadias in an effort to understand their distribution, frequency and impact on the development of hypospadias and generated a database for future research. The identification of novel CNVs and their potential pathogenic mechanisms provides valuable insights into the genetic underpinnings of this condition and paves the way for improved diagnostic and therapeutic strategies. The index family was optimal for such analysis in view of consanguineous marriage, availability of WES data in a quad family with more than one affected progeny and unaffected progeny as additional control, thereby enabling identification of de novo and inherited CNVs along with genotype-phenotype correlation.

The study has identified 2 de novo CNVs affecting the OR2J1 and OR14J1 genes expressed in testis and spermatozoa as major histocompatibility complex (MHC)-linked olfactory receptors. Additional CNVs encompassing genes known to be relevant to hypospadias such as GREM1, RRN3, KIAA0753 and HNF1B have also been identified and landscaped. Genes involved with the etiopathogenesis of hypospadias have been identified in the parents (phenotype: normal) supporting the theory of oligogenic or polygenic inheritance. Further research is needed to validate these findings and explore the functional implications of the identified CNVs in the pathogenesis of hypospadias.

Author Contribution

SK, JS, DG, RS, PL: Bioinformatic analysisVJ, AD, DKY, SA: Supervision, draft editing, discussions, etcMBS, HHA: Clinical material, data generation, primary analysisHS, NK: Conceptualisation, Draft editingPG: Idea, Data, collaboration, supervision, first draft, draft finalisation, interpretation of analysisAll authors reviewed the manuscript.

Acknowledgement

We thank the family investigated for their invaluable contribution to literature.

Data Availability

Sequence data that support the findings of this study with the European Nucleotide Archive with the primary accession code PRJNA982072

Ethics Statement: Public domain data downloaded from European Nucleotide Archive has been re-analysed hence ethical considerations are not relevant herein.
No photographs requiring consent for publication have been included.
All authors have contributed significantly to the manuscript as per the ICMJE guidelines.
None of the authors have any conflict of interest
The study has not received any funding

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Tables 1-3 are available in the Supplementary Files section.

No competing interests reported.

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Exploring Familial Hypospadias: Genetic Insights from Copy Number Variants in a Quad Family

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