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Identification of a novel FGF3 variant and a new phenotype in three LAMM syndrome families

BMC Medical Genomics volume 17, Article number: 254 (2024) Cite this article

Abstract

Over 700 syndromes associated with hearing loss (HL) have been identified. Labyrinthine aplasia, microtia, and microdontia (LAMM syndrome, OMIM: 610706) is a rare HL syndrome characterized by congenital sensorineural HL, labyrinthine aplasia, type I microtia and microdontia, which is caused by biallelic variants in the FGF3 gene. Using Whole-exome sequencing (WES), we identified a novel missense FGF3 variant (c.137G > C, p. Arg46Pro (NM_005247.4) in three unrelated Uyghur ethnic families. This variant is classified as a variant of uncertain significance according to ACMG guidelines, with the applied criteria of PM3, PM2_Supporting, PP3 and PP4. Patients from the three families revealed variable clinical features. We found a novel phenotype, sparse hair, in one of the proband. Our findings expanded the variant and phenotype spectrum of LAMM syndrome and provided new insights to the diagnose and pathogenesis investigation of the disease.

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Introduction

Hearing loss (HL) is one of the most prevalent sensory disorders that affects 1 to 2 per 1000 children at birth or during childhood [1]. About 60% of congenital HL are caused by genetic factors, 30% are acquired and 10% are idiopathic [2]. Syndromic HL refers to hearing impairment related to abnormalities that affect other organs/systems [3]. Up to now, over 700 syndromes associated with HL have been identified. Nearly 20% of congenital HL is syndromic [3, 4]. HL can be classified as conductive HL, which is related to abnormalities in the external or middle ear and sensorineural HL, which is caused by defects in the inner ear, auditory nerve or auditory cerebral cortex [5]. Structure defects in the inner ear occurs in 15-20% of cases with severe or profound sensorineural HL [6].

Labyrinthine aplasia, microtia, and microdontia (LAMM syndrome, OMIM: 610706) is a rare HL syndrome characterized by congenital sensorineural HL, labyrinthine aplasia, type I microtia and microdontia. It was first described by Tekin et al. in 2007 [7]. Variable features have been described in LAMM patients, including unilateral microtia and normal external ears, hypoplasia of alae nasi and involvement of the middle ear structures. Hearing phenotype of LAMM is typically congenital bilateral profound HL [8]. Although cognitive abilities are normal, patients often reported motor delay, due to absence of vestibular organs. Until now, the prevalence of LAMM syndrome (OMIM 610706, LAMM) has not been established [7].

LAMM is caused by FGF3 gene in an autosomal recessive manner. FGF3 gene, also called Int2 or HBGF-3, contains three exons and encodes a 239-amino-acid-long protein, fibroblast growth factor 3 [9]. FGF3 protein regulates morphogenesis, embryonic development, cell growth, and tumor development through the RAS/MAP kinase pathway [10, 11]. Both loss of function (nonsense, frameshift and splicing) and missense variants affecting highly conserved residues in FGF3 were found to cause LAMM [12,13,14]. Furthermore, Fgf3-null mouse models showed variable dorsal otic malformations, suggesting that LAMM syndrome is caused by loss of FGF3 functions [10].

In this study, we recruited three unrelated HL families with LAMM syndrome phenotypes. High throughput sequencing identified a novel missense FGF3 variant in all three families. Although sharing the same variant, patients from the three families showed variable clinical features.

Materials and methods

Cohort and clinical assessment

Three Uyghur ethnic families were recruited to the Hereditary Deafness Center at the Eye, Otolaryngology Hospital Affiliated with Fudan University, Shanghai, China. All individuals and family members underwent complete physical examination and were tested by pure-tone audiometry. Hearing thresholds were measured at the following frequencies: 0.125, 0.25, 0.5, 1, 2, 4, 6, and 8 kHz. Patients were examined to identify the inner ear defects by High-resolution magnetic resonance imaging (MRI) scans and High-Resolution CT. Fully informed written consents were provided by all family members. This study was approved by the ethics committee of the Institutional Review Board of the Eye, Ear, Nose and Throat Hospital affiliated with Fudan University (Shanghai, China).

Next-generation sequencing

Whole blood samples were collected, and genomic DNA was extracted using DNA Isolation Kit (Qia-Gen, Hilden, Germany). Probands were pre-screened for pathogenic variants in the GJB2 gene by Sanger sequencing, and no pathogenic variants were identified. All probands of the families underwent WES subsequently. A sequencing library was prepared using a DNA library preparation kit (New England Biolabs, lpswich, MA, catalogue#E6040). High-throughput sequencing was performed on Illumina Hiseq 2000 (Illumina, Inc., San Diego, CA). To validate the variant, PCR and sequencing primers were designed by Primer3 online software (http://bioinfo.ut.ee/primer3/). PCR and sequencing primers were designed using Primer3 online tools. Sanger sequencing was performed using Primer3 on a 3730XL (Applied Biosystems). The results of Sanger sequencing were aligned and viewed with the reference genome of the FGF3 gene using the Snapgene tool.

Variant prioritization and interpretation

Raw sequencing data was generated by the Illumina CASAVA v1.8 pipeline and aligned to the human reference genome (hg19) using the Burrows-Wheeler Aligner (BWA) program. Variant calling was done with GATK package v4.1.8.1. All variants were annotated using ANNOVAR software [15]. To identify the pathogenic variants, these variants were filtered out based on the following conditions: (1) low-coverage variants (depth < 10) (2) variants in the noncoding regions (3) synonymous variants in the coding region (4) variants with minor allele frequency (MAF) > 0.001 in several databases (1000 genome project, gnomAD v2.1.1) (5) variants labelled as “benign” in the ClinVar database [15].

In silico analysis of novel candidate variants and gene

The deleterious effect of variants was predicted by Variant Effect Scoring Tool (VEST4), ‘The Rare Exome Variant Ensemble Learner’(REVEL), (https://sites.google.com/site/revelgenomics/), Mendelian Clinically Applicable Pathogenicity (M-CAP) (https://bejerano.stanford.edu/mcap/), mutation tasting (https://www.mutationtaster.org), Mutpred2 (http://mutpred.mutdb.org/index.html) and AlphaMissense (https://alphamissense.hegelab.org). The Ensembl Genome Browser (http://grch37.ensembl.org/index.html) and OMIM (Online Mendelian Inheritance in Man) (http://www.ncbi.nlm.nih.gov/Omim/) were used to analyze all genes and variants. Variant interpretation was performed based on the American College of Medical Genetics and Genomics (ACMG) recommendations [16, 17]. The ACMG is a report issued for clinically indicated exome and genome sequencing, a minimum list of conditions, genism and variants are supposed to be evaluated and reported to the clinicians [17]. Protein sequences from various species were obtained through NCBI website (https://www.ncbi.nlm.nih.gov) and protein sequences from species were aligned using Clustal Omega in SnapGene. The 3D structure of the FGF3 protein was predicted by using the AlphFold Protein Structure Database (https://alphafold.ebi.ac.uk).

Results

Clinical presentation

Case 1

In family 1, the proband was a 6-year-old female with moderate to severe bilateral congenital HL, bilateral microtia and microdontia. She was the third of three children born to nonconsanguineous parents of Uyghur descent. Family history was negative and the pedigree of the family is shown in Fig. 1a. The proband showed bilateral microtia with a shortened upper half of auricles and anteverted ears. Large skin tags at the superior medial aspect of the helical rim were noted bilaterally (Fig. 2a). A long face as well as widely spaced teeth with loss of tooth height and thin enamel (compatible with microdontia) were observed (Fig. 2b and c). Her hair was thin and sparse. Audiogram revealed a moderately severe U-shaped middle-frequency hearing loss (Fig. 2d). MRI scan shows stenosis of the internal auditory canal (Fig. S5a). The results of the MRI illustrate an arachnoid cyst in cisterna occipitalis magnus, bilateral maxillary sinusitis, enlarged bilateral retropharyngeal lymph nodes.

Fig. 1
figure 1

The pedigrees of the three families. (a). The pedigree of the family (1) (b). The pedigree of the family (2) (c). The pedigree of the family (3) (Arrows indicate the probands)

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Fig. 2
figure 2

Clinical photographs of the affected individual in family 1. Note the presence of LAMM syndrome in this patient. (a). The prominent tip of the low set, anterverted, dysplastic left and right ears. (b). Sparse hair and a long face were observed. (c). Intraoral views show small widely spaced teeth and abnormal primary canines and molars. (d). Pure-tone audiogram with 125 Hz to 8000 Hz for affected proband (AC means air conduction, BC means bone conduction)

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Case 2

In family 2, the proband was a 10-year-old Uyghur ethnic female with complete labyrinthine aplasia, microtia, and microdontia. She was the first of two children born to consanguineous parents. Her 7-year-old brother was healthy. Family history was negative and the parents were first cousins. The pedigree of the family is shown in Fig. 1b. Bilateral microtia with shortened upper half of auricles and anteverted ears were observed. Large skin tags at the superior medial aspect of the helical rim were noted bilaterally (Fig. 3a). A long face, hypoplastic alae nasi as well as widely spaced teeth with loss of tooth height and thin enamel (compatible with microdontia) were observed (Fig. 3b and c). The audiogram revealed a severe U-shaped middle-frequency hearing loss (Fig. 3d). HRCT show stenosis of the internal auditory canal. Bilateral rudimentary otocysts are evident (Fig. S5b).

Fig. 3
figure 3

Clinical photographs of the affected individual in family 2. Note the presence of LAMM syndrome in this patient. (a). The prominent tip of the low set, anterverted, dysplastic left and right ears. (b). A long face and hypoplastic alae nasi were observed. (c). Intraoral views show small widely spaced teeth and abnormal primary canines and molars. (d). Pure-tone audiogram with 125 Hz to 8000 Hz for affected proband (AC means air conduction, BC means bone conduction)

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Case 3

In family 3, a 1-year-old male and a 12-year-old female were diagnosed with complete labyrinthine aplasia, microtia, and microdontia. Family history was negative and the parents were first cousins. The pedigree of the family is provided in Fig. 1c. The individual’s grandmothers are full sisters. The prominent tip of the low set, anteverted, dysplastic left and right ears were observed in the brother and his sister (Fig. 4a and c). Intraoral view shows small widely spaced teeth and abnormal primary canines and molars in the brother and his sister (Fig. 4b and d). Auditory brainstem response (ABR) tests of the proband and her affected brother showed no response at 97dBnHL intensity and the Auditory Steady-State Response (ASSR) tests for air conduction were shown in Fig. 4c. Axial HRCT obtained at the IAC level shows stenosis of the internal auditory canal (Fig. 5).

Fig. 4
figure 4

Clinical photographs of the affected individual in family 3. Note the presence of LAMM syndrome in the patients. (a, c). The prominent tip of the low set, anterverted, dysplastic left and right ears of the brother and sister respectively. (b, d). Intraoral views show small widely spaced teeth and abnormal primary canines and molars in the brother and his sister. (f). Auditory Steady-State Response (ASSR) tests for air conduction with 125 Hz to 8000 Hz for affected probands

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Fig. 5
figure 5

MR and CT images of 4 affected individuals with complete labyrinthine aplasia, microtia, and microdontia in 3 families. (a). Axial 3D FIESTA images at petrous bone levels show bilateral complete labyrinthine aplasia and the tracts for facial nerves (arrows) are present (family 1). (b). Axial CT images show bilateral rudimentary otocyst (arrows) (family 2). (c, d) Axial CT images show bilateral complete labyrinthine aplasia with hypoplastic petrous bone in 2 patients (family 3)

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Genetic diagnosis

WES was performed on the probands. A homozygous variant c.137G > C, p. Arg46Pro (NM_005247.4), was identified in exon 1 of the FGF3 gene in all probands of the three families. No pathogenic variants from other known HL genes were identified. This variant was validated by Sanger sequencing in all members of the family subsequently in three families. The c.137G > C variant leads to an amino acid substitution from arginine to proline at codon 46 (p. Arg46Pro) in FGF3. Sanger sequencing showed that all four patients were homozygous for this variant, while their parents were all heterozygous (PM3) (Figs. 6, 7 and 8). This variant is predicted to be harmful by multiple prediction tools (VEST4 score = 0.815) (PP3) and prediction results are listed in Table 1. This variant was extremely rare (frequency = 0.0000007) in the gnomAD v4.0.0 database (PM2_Supporting). Furthermore, all patients revealed phenotypes highly similar for LAMM syndrome (PP4). Therefore, this variant is classified as a variant of uncertain significance according to ACMG guidelines, with the applied criteria of PM3, PM2_Supporting, PP3 and PP4 [16, 17].

Table 1 Pathogenicity prediction results from multiple engines
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Fig. 6
figure 6

The results of the Sanger sequencing of the proband and her parents and one brother in family 1. The homozygous and heterozygous mutations were found in the proband and other members of this family respectively. The arrows indicate the variant c.137G > C

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Fig. 7
figure 7

The results of the Sanger sequencing of the proband and her parents and one brother in family 2. The homozygous and heterozygous mutations were found in the proband and other members of this family respectively. The arrows indicate the variant c.137G > C

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Fig. 8
figure 8

The results of the Sanger sequencing of the probands and parents in family 3. The homozygous and heterozygous mutations were found in the probands and other members of this family respectively. The arrows indicate the variant c.137G > C

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Bioinformatic analysis

The missense variant c.137G > C (p. Arg46Pro) substitutes Arginine with Proline, a nonpolar side chain amino acid, at codon 46 of the FGF3 protein. Arginine is highly conserved at codon 46 of FGF3 among different species (Fig. 9), supporting a pathogenic role for its substitution. Molecular modelling of the mutant protein was performed using Missense3D with AlphFold model AF-P11487-F1. It was suggested that the missense variant replaced a buried charged residue (Arginine) with an uncharged residue (Proline), which might disrupt the H-bonds formed by the original residue. Besides, the original Arginine has a high pLDDT score (95.96) (Fig. 10).

Fig. 9
figure 9

Arginine at position 46 of FGF3 is conserved in a variety of organisms from fish to frogs to humans. Protein data were collected at the National Center for Biotechnology Information Web site. Protein sequences were aligned using Clustal Omega in SnapGene

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Fig. 10
figure 10

3D protein structure prediction using AlphFold Protein Structure Database. (a) 3D protein structure prediction of Arginine in FGF3. (b). 3D protein structure prediction of Proline in FGF3

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Discussion

In this study, we recruited three unrelated families with LAMM syndrome. A novel missense variant in exon 1 of the FGF3 gene was identified. Although LAMM syndrome is mainly characterized by HL with labyrinthine aplasia, microtia, and microdontia, other features were also revealed by recent studies, including large skin tags, defect of the middle ear, hypoplastic alae nasi, stenosis of the jugular foramen, and absence or narrowing of the eighth cranial nerve [18]. Although all three families shared the same variant, their clinical manifestations varied. The proband from family 1 showed sparse hair which was not discovered in the other two families or previous LAMM cases. Patient in family 2 revealed hypoplastic alae nasi whereas the other two families were normal. These findings provide further evidence for the variable and diverse features of LAMM syndrome patients.

Until now, more than 24 pathogenic variants in the FGF3 gene have been associated with LAMM syndrome in databases and literature. We summarized known FGF3 variants in Table 2 [7, 12,13,14, 18,19,20,21,22,23,24,25,26]. The present study identified a novel missense variant (c.137G > C, p. Arg46Pro, NM_005247.4) in the FGF3 gene, results in the substitution of a highly conserved arginine by proline at amino acid 46 of the FGF3 protein. This variant lies at the start of the FGF domain (44 to 181aa) of FGF3 protein (Fig. 11), which may interrupt their interaction with the FGF ligands.

Table 2 Mutations found in FGF3 gene in the literature and databases
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Fig. 11
figure 11

The c.137G > C mutation spanning the FGF3 gene have been associated with LAMM syndrome. The FGF3 protein contains one highly conserved fibroblast growth factor (FGF) domain (amino acids 44–181), a predicted signal peptide (SP, amino acids 1–17), and a predicted transmembrane domain (TM, amino acids 72–92)

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The inner ear is differentiated from the ectodermal placode adjacent to the developing hindbrain [27]. It is reported that fibroblast growth factors are involved in otic placode induction and vesicle formation in the amphibian embryo [10, 27]. FGF3 is normally expressed in a hindbrain from otic induction through the endolymphatic duct outgrowth and also in the prospective neurosensory domain of the otic epithelium as morphogenesis initiates [27, 28]. Multiple phenotypic features have also been identified in the inner ear associated with various FGF3 pathogenic variants in the FGF3 knockout models [28]. FGF families, including FGF10 and FGF8 have also been shown to be involved in an FGF signaling cascade that is required in otic induction and morphogenesis in early ear development [27, 29].

Until now, the genotype-phenotype correlation of LAMM syndrome has not been thoroughly understood. In our study, variable features were observed among patients with the same variant from different families. Our study also suggested that the specific facial features (outer ear and wide space teeth, long face) could be used as diagnostic marker for LAMM syndrome. Sequencing of the FGF3 gene is considered as a diagnostic measure which can reduce diagnostic costs when individuals present such symptoms. The variant in this study might be a founder mutation for this isolated population for which consanguineous marriage is relatively common. In future study, the haplotype of the variant could be investigated by sequencing nearby SNPs. Furthermore, the frequency of this variant should be established in order to reduce future cases for the local population. However, there were no functional studies to investigate the function effects and the pathology of c.137G > C in FGF3. Instead, it is stated that additional studies are needed to show that the described variation is the responsible genetic pathology. Meanwhile, additional genotype-phenotype correlation studies will clarify the detailed phenotypic range caused by pathogenic variants in FGF3.

Conclusions

In summary, the present study identified a novel missense variant in the FGF3 gene associated with LAMM syndrome in three unrelated Uyghur ethnic families. Novel clinical features were found in one proband from family 1. These findings expanded the variant and phenotype spectrum of LAMM syndrome and provided new insights to the diagnose and pathogenesis investigation of the disease.

Nomenclature

The DNA nomenclature throughout is concurrent with HGVS Nomenclature Version 21.0.

Web resources

AlphaMissense, https://alphamissense.hegelab.org.

AlphFold Protein Structure Database, https://www.alphafold.ebi.ac.uk.

Ensembl databases, http://grch37.ensembl.org/index.html.

Mendelian Clinically Applicable Pathogenicity (M-CAP), http://bejerano.stanford.edu/mcap/.

Mutation tasting, https://www.mutationtaster.org.

Mutpred2, http://mutpred.mutdb.org/index.html.

Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/.

Rare Exome Variant Ensemble Learner’(REVEL), https://sites.google.com/site/revelgenomics/.

gnomAD v4.0.0 database, https://gnomad.broadinstitute.org.

Primer3, http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi.

Protein-protein BLAST, http://www.ncbi.nlm.nih.gov/blast/Blast.cg.

HGVS Nomenclature, https://hgvs-nomenclature.org.

Data availability

The variant has been submitted to the NCBI ClinVar database whose accession number is SCV004697337. The raw sequence datasets generated during the study are not publicly available because it is possible that individual privacy could be compromised but they are available from the corresponding author Luo Guo (guoluo.gary@foxmail.com) on reasonable request.

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Funding

This work was supported by the Natural Science Fund of Xinjiang Uygur Autonomous Region (2022D01F16), the National Natural Science Foundation of China (Nos. 82192860, 81620108005, 81500801, 81830029), the National Key R&D Program of China (Nos. 2017YFA0103900, 2016YFC0905200) and the Shanghai Municipal Health Commission (Nos. 201840277).

Author information

Author notes

  1. Qiang Du, Yike Zhang and Rujian Hong there authors contributed equally to this work.

Authors and Affiliations

  1. Department of the Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, ENT Institute and Otorhinolaryngology, Fudan University, Shanghai, 200031, China

    Qiang Du, Yike Zhang, Huawei Li & Luo Guo

  2. NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, China

    Qiang Du, Yike Zhang, Huawei Li & Luo Guo

  3. Department of Otorhinolaryngology, Kashi Prefecture Second People’s Hospital, Xinjiang Uygur Autonomous Region, Xinjiang, 844000, China

    Qiang Du, Nuermaimaiti Tulamaiti, Maiheba Abulaiti, Nueraili Awuti, Wulamu Wusiman, Xirinayi Alimu, Ayinuer Wusiman, Nueraihaimaiti Kadier, Huilin Li, Zhifei Zhang, Huan Qi & Ayituersun Abudukeyoumu

  4. Department of Radiology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China

    Rujian Hong & Zhipeng Xia

  5. Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Huawei Li

  6. Shanghai Engineering Research Centre of Cochlear Implant, Shanghai, 200031, China

    Huawei Li

  7. The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China

    Huawei Li

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Contributions

LG and HL designed the experiment. QD, YZ and RH carried out the experiments. QD, YZ and LG wrote the main manuscript text and prepared figures. All authors reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Huawei Li or Luo Guo.

Ethics declarations

Ethics approval and consent to participate

All procedures performed in this study involving human participants were performed in accordance with the Declaration of Helsinki. This study was approved by the Eye, Ear, Nose and Throat Hospital affiliated with Fudan University Review Board of the Office of Research Compliance through protocol 2017044. Written informed consent was obtained from adult participants involved in the study. Written informed consent was obtained from parents/guardians of all minor participants involved in the study. This study was approved by the ethics committee of the Institutional Review Board of the Eye, Ear, Nose and Throat Hospital affiliated with Fudan University (Shanghai, China).

Consent for publication

We confirm that parents of the patients signed written informed consent for publication of their own and children’s data and any accompanying images.

Competing interests

The authors declare no competing interests.

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Du, Q., Zhang, Y., Hong, R. et al. Identification of a novel FGF3 variant and a new phenotype in three LAMM syndrome families. BMC Med Genomics 17, 254 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12920-024-02023-1

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12920-024-02023-1

Keywords

BMC Medical Genomics

ISSN: 1755-8794

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