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FREM1 Autosomal Recessive Disorders

, MD, PhD, FRCPC, FCCMG and , MBBS, PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: May 1, 2025.

Estimated reading time: 23 minutes

Summary

Clinical characteristics.

FREM1 autosomal recessive disorders include Manitoba oculotrichoanal (MOTA) syndrome, bifid nose with or without anorectal and renal anomalies (BNAR) syndrome, and isolated congenital anomalies of kidney and urinary tract (CAKUT).

MOTA syndrome is characterized by an aberrant hairline (unilateral or bilateral wedge-shaped extension of the anterior hairline from the temple region to the ipsilateral eye) and anomalies of the eyes (widely spaced eyes, anophthalmia/microphthalmia and/or cryptophthalmos, colobomas of the upper eyelid, and corneopalpebral synechiae), nose (bifid or broad nasal tip), abdominal wall (omphalocele or umbilical hernia), and anus (stenosis and/or anterior displacement of the anal opening). The manifestations and degree of severity vary even among affected members of the same family. Growth and psychomotor development are normal.

BNAR syndrome is characterized by a bifid or wide nasal tip, anorectal anomalies, and kidney malformations (e.g., renal agenesis, renal dysplasia). Typically, the eye manifestations of MOTA syndrome are absent.

FREM1-related CAKUT has been reported in two boys from Macedonia with isolated CAKUT who had the same homozygous FREM1 pathogenic variants.

Diagnosis/testing.

The diagnosis of a FREM1 autosomal recessive disorder is established in a proband with biallelic pathogenic variants in FREM1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Intensive ocular lubrication to avoid exposure keratopathy before surgery is performed; release of synechiae between the eyelid and cornea; surgical intervention and/or prostheses for anophthalmia/microphthalmia and cryptophthalmos if warranted; supportive care for those with visual impairment. Rhinoplasty for notched ala nasi or bifid nose. Dilation for anal stenosis. Surgical closure of omphalocele; surgical or conservative management of umbilical hernia. Supportive treatment to preserve kidney function and electrolyte balance; dialysis and transplant if indicated in individuals with kidney failure. Psychosocial support and care coordination as needed.

Surveillance: Assess kidney function in those with kidney disease with frequency per nephrologist; social work and family support at each visit.

Genetic counseling.

Phenotypes caused by biallelic FREM1 pathogenic variants – including MOTA syndrome, BNAR syndrome, and FREM1-related CAKUT – are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a FREM1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the FREM1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

GeneReview Scope

FREM1 Autosomal Recessive Disorders: Included Phenotypes 1
  • Manitoba oculotrichoanal (MOTA) syndrome
  • Bifid nose with or without anorectal and renal anomalies (BNAR) syndrome
  • FREM1-related congenital anomalies of kidney and urinary tract (CAKUT)
1.

Nonsyndromic metopic craniosynostosis (OMIM 614485) due to heterozygous pathogenic variants in FREM1 is not included in the scope of this chapter (see Genetically Related Disorders).

Diagnosis

No consensus clinical diagnostic criteria for FREM1 autosomal recessive disorders have been published.

Suggestive Findings

A FREM1 autosomal recessive disorder should be suspected in an individual with clinical findings and/or family history of Manitoba oculotrichoanal (MOTA) syndrome, bifid nose with or without anorectal and renal anomalies (BNAR) syndrome, or congenital anomalies of kidney and urinary tract (CAKUT).

MOTA syndrome

  • Widely spaced eyes
  • Aberrant anterior hairline extending to the ipsilateral eye (unilateral or bilateral); often wedge-shaped, but may also resemble a thin stripe or appear tongue-shaped
  • Ocular abnormalities including ipsilateral colobomas of the upper eyelid (sometimes referred to as a Tessier number 10 cleft by surgeons), corneopalpebral synechiae (i.e., adhesions between the eyelids and the cornea), and microphthalmia/anophthalmia and/or cryptophthalmos. Corneal clouding was described in one individual. The upper eyelid colobomas and cryptophthalmos are part of a spectrum of anomalies ranging from colobomas of the lid to eyelid coloboma plus corneopalpebral synechiae (also known as abortive cryptophthalmos) to complete cryptophthalmos [Nouby 2002]. Anomalies may be unilateral or bilateral; the severity may differ between the two eyes.
  • Absent or interrupted eyebrow ipsilateral to the eye defect
  • Bifid nose, notch at the nasal tip, or broad nose
  • Anal stenosis and/or anteriorly placed anus
  • Omphalocele or umbilical hernia
  • Ethnic origin of aboriginal Oji-Cree

BNAR syndrome

  • Median nose cleft or notch, or wide bulbous nasal tip
  • Anorectal anomalies (e.g., anal stenosis, anteriorly placed anus)
  • Kidney malformations (e.g., renal agenesis, renal dysplasia)
  • Eye manifestations of MOTA syndrome typically absent

FREM1-related CAKUT. Kidney malformations (e.g., vesicoureteral reflux, renal hypodysplasia) [Kohl et al 2014]

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of a FREM1 autosomal recessive disorder is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in FREM1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic FREM1 variants of uncertain significance (or of one known FREM1 pathogenic variant and one FREM1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic findings suggest the diagnosis of a FREM1 autosomal recessive disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence analysis of FREM1 can detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
    Note: In individuals with Oji-Cree ancestry, gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications of FREM1 may be considered first. If only one or no pathogenic variant is found, sequence analysis of FREM1 can be performed.
  • A multigene panel that includes FREM1 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of a FREM1 autosomal recessive disorder has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in FREM1 Autosomal Recessive Disorders

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
FREM1 Sequence analysis 3~80%-90% 4
Gene-targeted deletion/duplication analysis 5~10%-20% 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Alazami et al [2009], Slavotinek et al [2011], Nathanson et al [2013], and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

6.

A deletion of exons 8 to 23 (c.824+627_3840-1311del) was identified in six individuals of Oji-Cree ancestry [Slavotinek et al 2011]. Several additional large deletions/duplications have been reported in individuals with FREM1 autosomal recessive disorders [Stenson et al 2020].

Clinical Characteristics

Clinical Description

Manitoba Oculotrichoanal (MOTA) Syndrome

Ocular abnormalities include ipsilateral colobomas of the upper eyelid (sometimes referred to as a Tessier number 10 cleft), corneopalpebral synechiae (i.e., adhesions between the eyelids and the cornea, also known as abortive cryptophthalmos), and microphthalmia/anophthalmia and/or cryptophthalmos. Anomalies may be unilateral or bilateral; the severity may differ between the two eyes.

Visual impairment may result directly from the ocular malformations or indirectly from exposure keratopathy. The long-term visual outcome depends on the severity of the ocular malformations and is poor for individuals with bilateral complete cryptophthalmos. In those with milder ocular malformations, such as upper eyelid colobomas, vision is typically intact.

Corneal clouding was described in one individual.

Anal anomalies include anal stenosis and/or anteriorly placed anus. No associated anomalies of the sacrum, vertebrae, or tethered cord have been reported. No affected individuals have had refractory constipation, fecal incontinence, or procedure-related stenosis or fistula.

Characteristic facial features include widely spaced eyes; an aberrant anterior hairline extending down to the ipsilateral eye (unilateral or bilateral) that is often wedge-shaped but may also resemble a thin stripe or appear tongue-shaped; ipsilateral absent or interrupted eyebrow; and a broad nose or notched or bifid nasal tip.

Omphalocele or umbilical hernia has been reported in approximately one third of affected individuals. Conservative management or surgical intervention for omphalocele or umbilical hernia is usually well tolerated, and outcomes are excellent. Long-term intestinal complications have not been described.

Other. Additional findings have been reported: renal pelviectasis, renal dysplasia, hydrometrocolpos and vaginal atresia, cutaneous syndactyly, and additional dysmorphic features (e.g., high forehead with a frontal upsweep of hair, dysplastic ears, maxillary hypoplasia, underdeveloped ala nasi, short philtrum, thin upper lip, and relative microstomia) [Slavotinek et al 2011, Mitter et al 2012, Nathanson et al 2013]. One infant born with right unilateral dysplastic kidney had Cohen grade IV anterior glottic web (75% occlusion), grade I subglottic stenosis (40% stenosis), and aphonia [Dahlquist et al 2024].

Growth and development. Individuals with MOTA syndrome assessed at various ages appear generally healthy with age-appropriate growth and cognition. Motor, social, and speech-language skills are typically normal, although development may be influenced by the presence of severe eye defects that lead to visual impairment.

The manifestations and degree of severity vary even among affected members of the same family.

Bifid Nose with or without Anorectal and Renal Anomalies (BNAR) Syndrome

BNAR syndrome was described in ten individuals from three consanguineous families of Egyptian, Afghani, and Pakistani origin [Al-Gazali et al 2002, Alazami et al 2009]. Subsequently, biallelic FREM1 pathogenic variants have been reported in several additional individuals with this phenotype [Brischoux-Boucher et al 2020, Berrada et al 2023, Chen et al 2023].

Craniofacial features include broad and/or bifid nose (100%), widely spaced eyes, aberrant hairlines, and short and thick oral frenula. Some individuals have only been found to have a broad and/or bifid nose [Brischoux-Boucher et al 2020, Chen et al 2023]. Colobomas similar to MOTA syndrome have been described [Berrada et al 2023], but typically the eye manifestations of MOTA syndrome are absent.

Kidney malformations (e.g., bilateral renal agenesis, unilateral renal agenesis) have been found in around two thirds (8/12) of individuals evaluated, although not all individuals have had kidney ultrasound examination. Unilateral renal agenesis is the most common kidney malformation [Chen et al 2023].

Anorectal malformations (e.g., anteriorly placed anus, anal stenosis) is comparatively rare, found in 2/13 individuals evaluated.

Airway malformations have been reported in 2/8 individuals evaluated.

FREM1-Related Congenital Anomalies of Kidney and Urinary Tract (CAKUT)

FREM1-related CAKUT has been reported in an individual with bilateral vesicoureteral reflux (VUR) grade III and in another individual with right-sided VUR grade V in conjunction with right-sided renal hypodysplasia [Kohl et al 2014].

Other Phenotypes

The following additional phenotypes have been reported in individuals with biallelic FREM1 pathogenic variants:

  • One individual was reported with isolated congenital diaphragmatic hernia [Beck et al 2013].
  • One fetus had severe hydrocephalus and shortened limbs associated with novel FREM1 pathogenic variants [Yang et al 2017].
  • One individual with bifid nose, facial cleft-like dysmorphism, aberrant hairline, and blepharon-coloboma was reported. [Gu et al 2021]
  • One individual with homozygous 9p22.3 deletion (encompassing FREM1 exons 19-30) was reported with Ebstein anomaly, mild intellectual disability, bifid nose, dental anomalies (midline diastema, abnormal size and shape of teeth), short oral frenula, low-set ears, and brachycephaly; his affected sister had a BNAR syndrome phenotype [Brischoux-Boucher et al 2020].
  • One individual with VACTERL had biallelic FREM1 pathogenic variants [Kolvenbach et al 2021].

Genotype-Phenotype Correlations

Genotype-phenotype correlations have not been possible to date given the rarity of the condition and limited number of pathogenic variants described.

Prevalence

The prevalence of FREM1 autosomal recessive disorders is unknown.

To date, the authors are aware of 30 published individuals with MOTA syndrome.

Based on the number of individuals identified to date in the aboriginal Oji-Cree community of the Island Lake region of northern Manitoba, Canada, which had a population of 4,685 in 1996 and 2,020 in 2001 [First Nation Profiles 2004], the incidence of MOTA syndrome in that population is estimated at 2-6:1,000 births; however, this may be an underestimate in this population, as a few presumably affected individuals have also been identified through family histories of affected individuals, and some individuals with less severe presentations may not have come to medical attention. All affected individuals from the Island Lake region identified to date are presumed to be related.

Differential Diagnosis

Disorders of known genetic cause in the differential diagnosis of Manitoba oculotrichoanal (MOTA) syndrome and bifid nose with or without anorectal and renal anomalies (BNAR) syndrome are listed in Table 2.

Table 2.

Genes of Interest in the Differential Diagnosis of MOTA Syndrome and BNAR Syndrome

Gene(s)DisorderMOIFeatures of Disorder
Overlapping w/MOTA &/or BNAR syndromeDistinguishing from MOTA & BNAR syndromes
ALX1
ALX3
ALX4 		Frontonasal dysplasia (OMIM PS136760)AR
  • Widely spaced eyes
  • Broad forehead
  • Widow's peak
  • Broad nasal root; absence of nasal tip formation; unilateral/bilateral cleft ala nasi 1
  • Absence of cryptophthalmos
  • Cranium bifidum 2
  • Absence of omphalocele & anorectal abnormalities
EFNB1 Craniofrontonasal dysplasia (OMIM 304110)XLIn females: 3
  • Widely spaced eyes
  • Broad nasal bridge, bifid nasal tip
  • Absence of cryptophthalmos
  • Craniosynostosis
  • Cranium bifidum
  • Absence of omphalocele & anorectal abnormalities
FRAS1
FREM2
GRIP1 		Fraser syndrome (OMIM PS219000)AR
  • Anophthalmia/microphthalmia, cryptophthalmos, eyelid colobomas, widely spaced eyes
  • Wedge-shaped lateral anterior hairline
  • Bifid nasal tip / notched ala nasi
  • Anal stenosis or imperforate anus 4
  • Cognitive impairment
  • Often early mortality
LRP2 Donnai-Barrow syndrome AR
  • Widely spaced eyes
  • Omphalocele
  • Agenesis of corpus callosum
  • Sensorineural hearing loss
  • Diaphragmatic hernia
MED12 FG syndrome type 1 (See MED12-Related Disorders.)XLIn male infants:
  • Widely spaced eyes
  • Anteriorly placed anus, anal stenosis
Often, additional findings such as:
  • Thumb anomalies
  • Vertebral abnormalities
SALL1 SALL1-related Townes-Brocks syndrome ADAnteriorly placed anus, imperforate anus, anal stenosis

AD = autosomal dominant; AR = autosomal recessive; BNAR = bifid nose with or without anorectal and renal anomalies; MOI = mode of inheritance; MOTA = Manitoba oculotrichoanal; XL = X-linked

1.
2.

Cranium bifidum is a midline defect of the frontal bone detected on skull radiographs.

3.

Craniofrontonasal dysplasia shows greater severity in heterozygous females than in hemizygous males. Typically, females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, a bifid nasal tip, and grooved nails; they may also have skeletal abnormalities. In contrast, males typically show only widely spaced eyes (see OMIM 304110).

4.

Disorders of unknown genetic cause in the differential diagnosis of MOTA syndrome and BNAR syndrome include:

  • Oculoauriculofrontonasal syndrome (OAFNS; OMIM 601452). Overlapping features include upper eyelid colobomas, widely spaced eyes, notched ala nasi or bifid nose, and normal intelligence. Features of OAFNS distinguishing the disorder from MOTA syndrome and BNAR syndrome include hemifacial microsomia, ear malformations, preauricular tags, epibulbar dermoids, and abnormalities of the frontal bone.
  • VACTERL association (OMIM 192350). Overlapping features include anteriorly placed anus and anal stenosis. Features of VACTERL association distinguishing the disorder from MOTA syndrome and BNAR syndrome include additional findings that are often present such as thumb and vertebral abnormalities.

Isolated congenital anomalies of kidney and urinary tract (CAKUT) has been associated with more than 50 genes to date and may be inherited in an autosomal dominant, autosomal recessive, or multifactorial manner [Nicolaou et al 2015, Kohl et al 2021]. The genetic etiology in most individuals with isolated CAKUT is unknown [Kohl et al 2014].

Management

No clinical practice guidelines for FREM1 autosomal recessive disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a FREM1 autosomal recessive disorder, the evaluations summarized in Table 3, Table 4, or Table 5 (depending on the phenotype), if not performed as part of the evaluation that led to the diagnosis, are recommended.

Treatment of Manifestations

Treatment of FREM1 autosomal recessive disorders consists primarily of surgical intervention with procedures tailored to the specific needs of the individual. A multidisciplinary team comprising a clinical geneticist, general surgeon, ophthalmologist, otolaryngologist, plastic surgeon, and social worker is preferred for optimal management.

Table 6.

FREM1 Autosomal Recessive Disorders: Treatment of Manifestations

Manifestation/
Concern		TreatmentConsiderations/Other
Colobomas of upper eyelids & synechiae Managed conservatively w/intensive ocular lubricationTo avoid exposure keratopathy before surgery is performed
Surgical release of synechiae
Anophthalmia/
microphthalmia & cryptophthalmos 		May warrant surgical intervention & insertion of prosthesesTo facilitate development of ocular region 1
Low vision services
  • Children: through early intervention programs &/or school district
  • Adults: low vision clinic &/or community vision services / OT / mobility services
Visual impairment (e.g., refractive errors) Treatment per ophthalmologistMay be assoc w/colobomas & corneopalpebral synechiae
Notched ala nasi or bifid nose RhinoplastyMay be performed for cosmetic purposes
Anal stenosis Serial dilations
Omphalocele & umbilical hernia May be managed conservatively or surgicallyTo date, all persons w/a FREM1 AR disorder managed surgically have tolerated the procedure w/o complications.
Anteriorly placed anus Managed conservatively or w/surgical interventionAs determined on individual basis
Kidney malformations
  • Supportive treatment to preserve kidney function & electrolyte balance
  • Surgical correction when indicated
Dialysis & transplant may be indicated in persons w/kidney failure.
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

AR = autosomal recessive; OT = occupational therapy

1.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

FREM1 Autosomal Recessive Disorders: Recommended Surveillance

System/ConcernEvaluationFrequency
Kidney malformations Imaging & kidney function assessmentIn those w/kidney disease w/frequency per nephrologist
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).At each visit

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Phenotypes caused by biallelic FREM1 pathogenic variants – including Manitoba oculotrichoanal (MOTA) syndrome, bifid nose with or without anorectal and renal anomalies (BNAR) syndrome, and FREM1-related congenital anomalies of kidney and urinary tract (CAKUT) – are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • If both parents are known to be heterozygous for a FREM1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) do not have MOTA syndrome, BNAR syndrome, or FREM1-related CAKUT.

Offspring of a proband. The offspring of an individual with a FREM1 autosomal recessive disorder are obligate heterozygotes (carriers) for a FREM1 pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a FREM1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the FREM1 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
  • Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with a FREM1 autosomal recessive disorder, particularly if both partners are of the same ancestry. The incidence of MOTA syndrome in the Oji-Cree community of the Island Lake region of northern Manitoba, Canada, is estimated at 2-6:1,000 births.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the FREM1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Ultrasound examination may be diagnostic of MOTA syndrome if findings such as omphalocele, cryptophthalmos, anophthalmia/microphthalmia, widely spaced eyes, and/or a broad nose are detected in a fetus known to be at increased risk for a FREM1 autosomal recessive disorder. However, mild findings may be difficult to detect on prenatal imaging.

Pregnancies at low a priori risk. Consideration of genetic disorders with findings similar to MOTA syndrome (see Differential Diagnosis) should be considered when hypertelorism, unilateral or bilateral underdeveloped eye or eyes, broad or bifid nose, omphalocele, and kidney malformation are identified on fetal ultrasound examination in a pregnancy not known to be at risk for MOTA syndrome.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

FREM1 Autosomal Recessive Disorders : Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
FREM1 9p22​.3 FRAS1-related extracellular matrix protein 1 FREM1 database FREM1 FREM1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for FREM1 Autosomal Recessive Disorders (View All in OMIM)

248450MANITOBA OCULOTRICHOANAL SYNDROME; MOTA
608944FRAS1-RELATED EXTRACELLULAR MATRIX PROTEIN 1; FREM1
608980BIFID NOSE WITH OR WITHOUT ANORECTAL AND RENAL ANOMALIES; BNAR

Molecular Pathogenesis

FREM1 encodes FRAS1-related extracellular matrix protein 1 (FREM1), which is a member of the FRAS1/FREM family of extracellular matrix proteins that are located in the sublamina densa of epithelial basement membranes during embryogenesis [Pavlakis et al 2011]. FREM1 forms a ternary complex with FRAS1, FREM2, and FREM3, which have similar functional domains and structures [Pavlakis et al 2011]. The ternary complex is critical for maintenance of epithelial-mesenchymal cohesion during embryonic development in mammals [Pavlakis et al 2011]. FREM1 pathogenic variants in humans are predicted to disturb the interactions with the proteins in this complex, although the levels of FRAS1 and FREM2 are not decreased [Vissers et al 2011]. Loss or disruption of the ternary complex is thought to reduce epithelial-mesenchymal adhesion during development, with subsequent generation of the characteristic clinical findings associated with Fraser syndrome and the FREM1 autosomal recessive disorders [Chacon-Camacho et al 2017].

Mechanism of disease causation. All pathogenic variants reported to date in FREM1 are hypothesized to result in loss of function.

Table 8.

FREM1 Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide Change
(Alias 1)		Predicted Protein ChangeComment [Reference]
NM_144966​.5
NP_659403​.4 		c.824+627_3840-1311del
(IVS7+631_IVS23-1311 del; del8-23 exon)		p.385_1327delCommon deletion assoc w/MOTA syndrome in Oji-Cree [Slavotinek et al 2011]

MOTA = Manitoba oculotrichoanal

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Chapter Notes

Author Notes

Chumei Li (ac.retsamcm@muhcil) is interested in hearing from clinicians treating individuals with a suspected FREM1-related disorder in whom no causative FREM1 variant has been identified.

Anne Slavotinek (gro.cmhcc@kenitovals.enna) is actively involved in clinical research regarding individuals with MOTA syndrome and Fraser syndrome. She would be happy to communicate with persons who have any questions regarding diagnosis of these conditions or other considerations.

Author History

Albert E Chudley, MD, FRCPC, FCCMG; University of Manitoba (2011-2019)
Chumei Li, MD, PhD, FRCPC, FCCMG (2008-present)
Anne Slavotinek, MBBS, PhD (2011-present)

Revision History

  • 1 May 2025 (sw) Comprehensive update posted live
  • 9 May 2019 (sw) Comprehensive update posted live
  • 13 October 2011 (me) Comprehensive update posted live
  • 9 July 2008 (me) Review posted live
  • 16 May 2008 (cl) Original submission

References

Literature Cited

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