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other·epidemiology, genetics, pediatric endocrinology, animal science·PMC10752378

Identification of novel genes including NAV2 associated with isolated tall stature

Frontiers in Endocrinology · 11 authors, 5 centres

AI SUMMARY

FIDELITY 94%

POPULATIONA three-generation family with extreme tall stature (index case height 208.6 cm, 4.0 SDS; other tall members: II.4 and III.1 with heights 3.2 SDS and 2.8 SDS) and a previously reported Dutch tall family.

INTERVENTIONWhole exome sequencing and variant filtering; functional analysis via CRISPR/Cas9 knockout of nav2 in Xenopus laevis; expression analysis in mouse growth plates.

COMPARISONTall family members vs. a normal-statured family member (III.2, height -0.7 SDS) and a normal Non-Finnish control cohort from gnomAD.

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TL;DR

This study identifies six novel candidate genes for isolated tall stature in a three-generation family, with NAV2, IFT140, and SCAF11 showing the strongest evidence through GWAS, growth plate expression analysis, and network analysis. CRISPR/Cas9 knockout of the NAV2 ortholog in Xenopus laevis resulted in a small (1–4%) but statistically significant increase in tadpole body length, supporting a role in growth regulation. These findings suggest oligogenic inheritance of tall stature and highlight NAV2 as a key player in longitudinal bone growth.

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**Background:** Isolated tall stature, defined as height above the 97.7th percentile, is often familial but lacking a known genetic cause. Pathological etiologies are rare (e.g., endocrine tumors, monogenic syndromes). Most cases are labeled idiopathic or familial tall stature, and monogenic causes are seldom identified, suggesting an oligogenic basis. Genome-wide association studies (GWAS) have identified thousands of height-associated loci, but few are diagnostic. This study aimed to identify novel genetic variants in a three-generation family with extreme tall stature, using whole exome sequencing and multiple lines of evidence to prioritize candidate genes.

**Methods:** Exome sequencing was performed on four tall individuals (I.1, II.1, II.4, III.1) from a three-generation family. Variants were filtered for shared presence among tall members, absence in a normal-statured family member (III.2), predicted damaging by Provean, SIFT, or PolyPhen-2, and a CADD score >15. Six candidate genes were identified: CNGB1, GGTLC2, HSD3B2, IFT140, NAV2, and SCAF11. Additional support was obtained from: (1) GWAS association with height using the Disease Knowledge Portal (p-values 10^-11 to 10^-14 for IFT140, NAV2, SCAF11); (2) Ingenuity Pathway Analysis (IPA) network analysis connecting these genes to known height-related genes; (3) mRNA expression analysis in murine growth plates (1-week-old vs. 4-week-old, and zonal comparisons) using microarray and RNA-Seq; (4) functional studies in Xenopus laevis via CRISPR/Cas9 knockout of nav2 using two sgRNAs targeting conserved exons; (5) re-examination of exome data from a previously reported Dutch tall family. Body length of tadpoles at stage 44-45 was measured from mouth to tail tip, normalized to controls, and analyzed with Wilcoxon rank-sum test.

**Key Results:** Six missense variants were shared by all tall family members and absent in the normal-statured member III.2: CNGB1 p.G1039R (allele frequency 5.4x10^-3), GGTLC2 p.G116V (9.4x10^-5), HSD3B2 p.A167V (1.6x10^-3), IFT140 p.R1433C (1.3x10^-3), NAV2 p.R2142C (3.7x10^-3), SCAF11 p.R983Q (4.7x10^-5). GWAS showed significant height association for IFT140, NAV2, and SCAF11. IPA network analysis indicated interactions between IFT140 and CRK, NAV2 and YWHAE/KRAS/HRAS/TRAP, and SCAF11 with ESR1/TCF7. Growth plate expression revealed that Ift140 and Nav2 were highly expressed compared to soft tissues. Nav2 showed the most pronounced spatial regulation: a fold change of -2.78 (p=1.91E-62) from proliferative to hypertrophic zone, and a temporal decrease in proliferative zone from 1 to 4 weeks (fold change -1.05, p=0.003). In Xenopus, nav2 knockout with sgRNA1 (35% mutagenesis) led to increased body length in all three experiments (Exp1: +0.97%, Exp2: +3.36%, Exp3: +4.23%). Combined normalized data showed a statistically significant increase (p=0.023). sgRNA2 (75-93% mutagenesis) caused organ defects and edemas in ~50% of embryos, but the unaffected 50% also showed mild, non-significant length increases (+0.47%, +1.49%). Additionally, a rare NAV2 variant (p.E2038K, CADD 26.8) was identified in two unrelated tall individuals from a Dutch family, further supporting its role.

**Clinical Implications:** This study provides evidence that isolated tall stature can arise from an oligogenic combination of rare, damaging variants, with NAV2 emerging as a strong candidate. The identification of NAV2, IFT140, and SCAF11 as novel height-associated genes expands our understanding of growth plate biology and may lead to new diagnostic markers for familial tall stature. Functional validation in Xenopus demonstrates that even subtle alterations in gene dosage (partial knockout) can modestly enhance growth, supporting the concept that multiple small-effect variants collectively drive extreme tall stature. These findings may eventually guide genetic counseling and management of families with unexplained tall stature, although further replication in larger cohorts and functional studies in mammalian models are needed to confirm causality and explore therapeutic implications.

PICO

PPOPULATION

A three-generation family with extreme tall stature (index case height 208.6 cm, 4.0 SDS; other tall members: II.4 and III.1 with heights 3.2 SDS and 2.8 SDS) and a previously reported Dutch tall family.

IINTERVENTION

Whole exome sequencing and variant filtering; functional analysis via CRISPR/Cas9 knockout of nav2 in Xenopus laevis; expression analysis in mouse growth plates.

OOUTCOME

Identification of shared rare missense variants in six genes (CNGB1, GGTLC2, HSD3B2, IFT140, NAV2, SCAF11); NAV2 knockout led to increased body length in Xenopus (combined normalized p=0.023); growth plate expression highlighted Nav2 as highly expressed and downregulated from proliferative to hypertrophic zones (fold change -2.78, p=1.91E-62).

STUDY TYPE

other

SPECIALTY

epidemiology

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FIDELITY CHECK

94% · A

ORIGINAL PAPER

PMC10752378

Identification of novel genes including NAV2 associated with isolated tall stature

Frontiers in Endocrinology

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ABSTRACT

Abstract Very tall people attract much attention and represent a clinically and genetically heterogenous group of individuals. Identifying the genetic etiology can provide important insights into the molecular mechanisms regulating linear growth. We studied a three-generation pedigree with five isolated (non-syndromic) tall members and one individual with normal stature by whole exome sequencing; the tallest man had a height of 211 cm. Six heterozygous gene variants predicted as damaging were shared among the four genetically related tall individuals and not present in a family member with normal height. To gain insight into the putative role of these candidate genes in bone growth, we assessed the transcriptome of murine growth plate by microarray and RNA Seq. Two ( Ift140, Nav2 ) of the six genes were well-expressed in the growth plate. Nav2 ( p -value 1.91E-62) as well as Ift140 ( p -value of 2.98E-06) showed significant downregulation of gene expression between the proliferative and hypertrophic zone, suggesting that these genes may be involved in the regulation of chondrocyte proliferation and/or hypertrophic differentiation. IFT140, NAV2 and SCAF11 have also significantly associated with height in GWAS studies. Pathway and network analysis indicated functional connections between IFT140 , NAV2 and SCAF11 and previously associated (tall) stature genes. Knockout of the all-trans retinoic acid responsive gene, neuron navigator 2 NAV2 , in Xenopus supports its functional role as a growth promotor. Collectively, our data expand the spectrum of genes with a putative role in tall stature phenotypes and, among other genes, highlight NAV2 as an interesting gene to this phenotype. Keywords: isolated tall stature, growth plate, NAV2, all-trans retinoic acid, oligogenic inheritance, IFT140, Xenopus

CITATION EXPORT

Birgit Weiss, Tim Ott, Philipp Vick et al.. Identification of novel genes including NAV2 associated with isolated tall stature. Frontiers in Endocrinology. (2023). https://doi.org/10.3389/fendo.2023.1258313

AUTHORS

11 · 5 CENTRES

Birgit Weiss, Tim Ott, Philipp Vick, Julian C Lui, Ralph Roeth, Sebastian Vogel, Stephan Waldmüller, Sandra Hoffmann, Jeffrey Baron, Jan M Wit, Gudrun A Rappold

1 Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
2 Department of Zoology, University of Hohenheim, Stuttgart, Germany
3 National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
4 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
5 Division of Pediatric Endocrinology, Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands