Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos, and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance was assumed because ... Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos, and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance was assumed because of consanguinity in the Oji-Cre population of Manitoba in which the syndrome was first described (summary by Slavotinek et al., 2011).
In 3 male and 3 female Manitoba Indian children, Marles et al. (1992) observed an apparently new autosomal recessive syndrome manifested by hypertelorism and a variable combination of unilateral eye malformations, aberrant anterolateral scalp hairline, and nasal and ... In 3 male and 3 female Manitoba Indian children, Marles et al. (1992) observed an apparently new autosomal recessive syndrome manifested by hypertelorism and a variable combination of unilateral eye malformations, aberrant anterolateral scalp hairline, and nasal and anal anomalies. The children belonged to 4 related families. The parents and 7 other sibs were clinically unaffected. The family histories were otherwise unremarkable. Pictured were several examples of a curious finding of an anomalous wedge of scalp hair extending in the left frontotemporal region to the eyebrow. The eye malformations included unilateral clinical anophthalmia, obstruction of the nasolacrimal ducts, and coloboma of the medial half of the upper eyelid. The anus was stenotic in one, anteriorly displaced in another, and both anteriorly displaced and stenotic in a third. Fryns (2001) described a 36-year-old woman who was born with bilateral microblepharon/ablepharon of the upper eyelids without apparent associated malformations. At 16 years of age, gynecologic examination for primary amenorrhea revealed vaginal atresia with the uterine cervix not in connection with the perineum. Laparoscopy demonstrated normal internal genital structures, and renal echography and cystography were normal. Examination in adulthood showed, in addition to microblepharon and subsequent corneal clouding, a high forehead with frontal hair upsweep, high nasal root with maxillary hypoplasia, small alae nasi with coloboma formation, short philtrum with thin upper lip, relative microstomia, and high palate. There were no clinical signs of ectodermal dysplasia. Li et al. (2007) reported 7 new patients with clinical findings consistent with MOTA syndrome from the Cree/Ojibway kindred previously described by Marles et al. (1992). Two of the patients had bilateral rather than unilateral abnormal anterior hairline patterns, and omphalocele was present in 3 patients. The authors also reported the first case of probable MOTA syndrome outside the native population of Island Lake, Manitoba in a female Dutch infant, born of nonconsanguineous parents, who had colobomata of the upper eyelids, cloudy left cornea, some excess hair extending to the left upper eyelid, broad columella, and broad nasal tip with palpable groove. Li et al. (2007) stated that the most consistent features were hypertelorism and a broad or notched tip of the nose. Yeung et al. (2009) described second-cousin male and female infants affected by a craniofacial abnormality similar to that seen in so-called 'Tessier number 10' clefts (Tessier, 1976) and in MOTA syndrome. The male infant, born of nonconsanguineous unaffected parents of Greek and Malaysian ancestry, was noted at birth to have bilateral symmetric upper eyelid colobomas, with absence of the medial two-thirds of the lid. There was disruption of the middle segment of the eyebrows and an unusual hairline, with a projection of hair in the temporal regions pointing toward the colobomas. There was hypertelorism and a broad nasal tip. Vision was assessed as normal. There were no anorectal anomalies, and the remainder of the examination was normal. The female infant, born to nonconsanguineous Greek parents, was noted at birth to have an extensive coloboma of the left upper eyelid, with absence of the medial two-thirds of the eyelid. An associated ipsilateral tongue of hair pointed to the coloboma, and there was also disruption of the middle part of the eyebrow. The right eye and surrounding soft tissues were normal, as was the remainder of the clinical examination. Yeung et al. (2009) noted that Tessier number 10 clefts previously had been only reported as sporadic cases and that the underlying etiology was believed to be environmental, but the familial clustering of these facial features and the variable association with other congenital anomalies supported a genetic rather than environmental cause. Slavotinek et al. (2011) reported another Oji-Cre family in which the eldest affected sister had a bifid nasal tip and a V-shaped wedge of hair on her left forehead. She had 2 younger sisters who were also affected, 1 with anophthalmia of the left eye and a similar V-shaped wedge of hair, and 1 with bifid nasal tip and prominent central vein. Another sister was unaffected. A male second cousin had bilateral cryptophthalmos with abnormal ocular globes, frontal extension of his hairline bilaterally, broad nasal bridge with mildly widened nasal tip, omphalocele, and anal stenosis. Ultrasound in the newborn period showed mild renal pelviectasis. At 4.75 years of age, he had mild to moderate delays but could walk and speak in sentences. There was no history of consanguinity, and this family was not known to be related to the Cree/Ojibway kindred previously reported by Li et al. (2007). - Clinical Variability Slavotinek et al. (2011) noted that eye defects occurred consistently in patients with MOTA syndrome but had not been reported in BNAR patients, and that conversely, renal agenesis appeared to be characteristic of BNAR but had not been observed in MOTA syndrome. However, although these findings enabled distinction between BNAR and MOTA in some patients, Slavotinek et al. (2011) stated that other patients exhibited more clinical overlap and could be diagnosed with either syndrome.
Noting phenotypic overlap between Fraser syndrome (219000) and MOTA, Slavotinek et al. (2006) analyzed the FRAS1 gene (607830) in 2 patients with MOTA (patients 3 and 4 of Li et al. (2007)) but did not identify any mutations. ... Noting phenotypic overlap between Fraser syndrome (219000) and MOTA, Slavotinek et al. (2006) analyzed the FRAS1 gene (607830) in 2 patients with MOTA (patients 3 and 4 of Li et al. (2007)) but did not identify any mutations. In a male patient from an Oji-Cre family with MOTA syndrome mapping to the FREM1 gene (608944) and 2 patients from the Cree/Ojibway kindred previously described by Li et al. (2007), Slavotinek et al. (2011) identified homozygosity for a 60.1-kb deletion including exons 8 to 23 of the FREM1 gene (608944.0004). In 3 affected sisters, second cousins to the male Oji-Cre patient, Slavotinek et al. (2011) identified compound heterozygosity for 16-exon deletion and a splice site mutation that led to skipping of exon 31. However, the same splicing pattern was seen in cDNA from a control fibroblast cell line, thus the authors concluded that this sequence variant was not pathogenic and stated that the second mutation in the 3 sisters remained undetected. In a woman with bilateral eyelid coloboma and vaginal atresia, originally reported by Fryns (2001), Slavotinek et al. (2011) identified homozygosity for a 4-bp deletion in the FREM1 gene (608944.0005), and in another MOTA patient, originally reported by Li et al. (2007), they identified compound heterozygosity for missense mutations in FREM1 (608944.0006 and 608944.0007). However, analysis of the FREM1 gene in the 2 cousins with MOTA reported by Yeung et al. (2009) revealed no mutation, and segregation analysis indicated that the affected children did not share a FREM1 allele from a common ancestor, making a causative role of FREM1 very unlikely in that family.
Diagnosis of Manitoba oculotrichoanal (MOTA) syndrome is based on the following [Marles et al 1992, Li et al 2007]....
DiagnosisClinical DiagnosisDiagnosis of Manitoba oculotrichoanal (MOTA) syndrome is based on the following [Marles et al 1992, Li et al 2007].Clinical features present in 50% or more of individuals with MOTA syndrome diagnosed to date: Ocular hypertelorism Aberrant anterior hairline extending to the ipsilateral eye (unilateral or bilateral); often wedge-shaped, but may also resemble a thin stripe or appear tongue-shapedWide nares, notched nares; bifid or broad nasal tipOcular 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), 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 defectAnal stenosis and/or anteriorly placed anus Omphalocele or umbilical hernia in approximately one third of affected individuals Minimum diagnostic criteria should include ocular hypertelorism and EITHER:Two or more additional features; OROne additional feature plus a previously affected full sib, parental consanguinity, or Island Lake aboriginal ethnicity.Supportive findings include the following: A positive family history consistent with autosomal recessive inheritance (i.e., an affected full sib and/or consanguinity); helpful but not necessary for the diagnosisEthnic origin of aboriginal Oji-Cree. To date, most (not all) affected individuals have been Oji-Cree, descended from the highly inbred population living in the Island Lake region of northern Manitoba, Canada (see Prevalence).Molecular Genetic TestingGene. FREM1 is the only gene in which mutations are known to cause Manitoba oculotrichoanal syndrome [Slavotinek et al 2011].Evidence for locus heterogeneity. No mutations in FREM1 were identified in two individuals with MOTA syndrome who were second cousins [Yeung et al 2009], suggesting genetic heterogeneity.TestingSequence analysis. FREM1 mutations were identified by genomic sequencing in 2/8 individuals with MOTA syndrome [Slavotinek et al 2011]. Deletion/duplication analysis. In 6/8 individuals with FREM1-confirmed MOTA syndrome a deletion of exons 8 to 23 (c.824+631_c.3840-1311del) was identified as causative [Slavotinek et al 2011]; the deletion is unlikely to be detected by sequence analysis of the coding and flanking intronic regions of genomic DNA, as the breakpoints are intronic. The deletion was detected initially using a single nucleotide polymorphism (SNP) array capable of detecting copy number differences, but may be identified by a variety of deletion/duplication analysis methods (Table 1, footnote 3). Table 1. Summary of Molecular Genetic Testing Used in Manitoba Oculotrichoanal SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityFREM1Sequence analysisSequence variants 22/8 Research onlyDeletion / duplication analysis 3Exonic or whole-gene deletions6/8 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband The diagnosis is primarily established by clinical findings.In individuals with Oji-Cree ancestry, deletion analysis of FREM1 may be considered first.In those individuals of other ethnicities or in whom no deletion or duplication of FREM1 is found, sequence analysis of FREM1 may be considered.Carrier testing for at-risk relatives requires prior identification of both disease- causing mutations in an affected family member. Note: Carriers are heterozygotes for this autosomal recessive disorder and to date are not known to be at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersBifid nose, renal agenesis, and anorectal malformation (BNAR) syndrome [OMIM 608980] is also associated with mutations in FREM1 [Alazami et al 2009]. In addition to the characteristic findings of bifid nose (100%), renal malformations (66%) and anorectal malformations (22%), airway malformations (22%), short and thick oral frenulae and incurved fifth toes have been observed in individuals with BNAR syndrome [Alazami et al 2009]. A broad/bifid nose has also been observed without accompanying hypertelorism in an individual with BNAR syndrome [Alazami et al 2009]. Mutations in FREM1 were found by genomic sequencing in 3/3 individuals with BNAR syndrome [Alazami et al 2009]. No exonic or whole-gene deletions have been described in individuals with BNAR syndrome to date.Three homozygous mutations have been reported in association with BNAR syndrome: c.1945C>T, predicting p.Arg649Trp; c.2721delG, predicting p.Val908Serfs*17; and c.4318G>A, predicting p.Gly1440Ser [Alazami et al 2009]. These mutations are all located in one of the 12 chondroitin sulfate proteoglycan (CSPG) domains of FREM1 [Alazami et al 2009] and are predicted to result in loss of function.
Manitoba oculotrichoanal (MOTA) syndrome is characterized by the findings detailed in Diagnosis. Additional findings have been reported in one individual each [Slavotinek et al 2011]: renal pelviectasis; vaginal atresia; and mild craniofacial dysmorphism (high forehead with a frontal upsweep of hair, maxillary hypoplasia, small nasal alae with colobomas and a bifid nasal tip, short philtrum, thin upper lip, and relative microstomia). ...
Natural HistoryManitoba oculotrichoanal (MOTA) syndrome is characterized by the findings detailed in Diagnosis. Additional findings have been reported in one individual each [Slavotinek et al 2011]: renal pelviectasis; vaginal atresia; and mild craniofacial dysmorphism (high forehead with a frontal upsweep of hair, maxillary hypoplasia, small nasal alae with colobomas and a bifid nasal tip, short philtrum, thin upper lip, and relative microstomia). The manifestations and degree of severity vary even among affected members of the same family. Not all features are observed in all affected individuals.Pregnancy of an affected infant is usually uneventful and birth weight, length, and head circumference are appropriate for gestational age. In one instance oligohydramnios was detected on prenatal ultrasound for an individual given a postnatal clinical diagnosis of MOTA syndrome with no detectable FREM1 mutation [Slavotinek et al 2011].Visual impairment may result directly from ocular malformation or indirectly from exposure keratopathy. The long-term visual outcome depends on the severity of the ocular malformation and is poor for individuals with bilateral complete cryptophthalmos. In those with milder ocular malformations, such as upper eyelid colobomas, vision is typically intact.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.The anteriorly displaced anus and anal stenosis are not associated with anomalies of the sacrum, vertebrae, or a tethered cord. No affected individuals have had refractory constipation, fecal incontinence, or procedure-related stenosis or fistula.Individuals with MOTA syndrome assessed at various ages appear generally healthy with age-appropriate growth and cognition. Motor, social, and speech and language skills are typically normal, although development may be influenced by the presence of severe eye defects leading to visual impairment. Individuals with MOTA syndrome have not had malformations of the limbs, spine, heart, lungs, or other internal organs. They have had normal skull x-rays with no evidence of cranium bifidum, a midline defect in the frontal bone found in the related condition, frontonasal dysplasia (FND) sequence.
Genotype-phenotype correlations have not been possible to date given the rarity of the condition and limited number of mutations described. ...
Genotype-Phenotype CorrelationsGenotype-phenotype correlations have not been possible to date given the rarity of the condition and limited number of mutations described.
Conditions with similar ocular findings, either on prenatal imaging or postnatal examination that may be confused with Manitoba oculotrichoanal (MOTA) syndrome include those with ocular hypertelorism, coloboma of the eyelids, anophthalmia/microphthalmia, cryptophthalmos, and omphalocele....
Differential DiagnosisConditions with similar ocular findings, either on prenatal imaging or postnatal examination that may be confused with Manitoba oculotrichoanal (MOTA) syndrome include those with ocular hypertelorism, coloboma of the eyelids, anophthalmia/microphthalmia, cryptophthalmos, and omphalocele.Ocular hypertelorism occurs in more than 500 disorders [Dollfus & Verloes 2004].The etiology of anophthalmia/microphthalmia includes chromosomal, teratogenic, and monogenic disorders [Verma & FitzPatrick 2007]. More than 200 entries that include microphthalmia are listed in OMIM (see Anophthalmia/Microphthalmia Overview).The following conditions need to be distinguished from MOTA syndrome:BNAR (bifid nose, renal agenesis and anorectal malformation) syndrome is allelic to MOTA syndrome (see Genetically Related Disorders). Fraser syndrome (also known as cryptophthalmos syndrome). Phenotypic overlap between Fraser syndrome [Slavotinek & Tifft 2002, McGregor et al 2003, Vrontou et al 2003] and MOTA syndrome includes cryptophthalmos, eyelid colobomas, anophthalmia/microphthalmia, a wedge-shaped lateral anterior hairline, hypertelorism, a bifid nasal tip/notched nares and anal stenosis or imperforate anus. Both conditions are inherited in an autosomal recessive manner and are more likely in consanguineous unions because of their rarity in the general population. However, persons with MOTA syndrome have not had syndactyly, ambiguous genitalia, cognitive impairment, ear anomalies, or limb anomalies and they do not fulfill the clinical diagnostic criteria for Fraser syndrome [Slavotinek & Tifft 2002, van Haelst & Scambler 2007]. MOTA syndrome is compatible with life and cognitive development is generally normal. In comparison, early mortality is frequently observed in individuals with Fraser syndrome. Mutations in FRAS1 (OMIM 607830) and FREM2 (OMIM 608945) cause Fraser syndrome [McGregor et al 2003, Jadeja et al 2005]. Mutations in FRAS1 have not been found in individuals with MOTA syndrome [McGregor et al 2003; Slavotinek et al 2006; Tukun, personal communication]. No data concerning sequence analysis of FREM2 in individuals with MOTA syndrome are available.Frontonasal dysplasia (FND) sequence, also known as median cleft face syndrome, is characterized by a broad forehead, widow's peak, ocular hypertelorism, and nostrils that range from notched to completely divided [Jones 2006]. Cranium bifidum, a midline defect of the frontal bone detected on skull x-rays, is also a common feature. The genetic etiology is complex: X-linked, autosomal recessive, and autosomal dominant inheritance have all been described [Nevin et al 1999, Koçak & Ceylaner 2009]. Recently, mutations in the homeobox-containing genes ALX1 and ALX3 have been found to cause autosomal recessive FND sequence [Twigg et al 2009, Uz et al 2010]. Craniofrontonasal dysplasia (CFND) shares craniofacial features with FND sequence but also includes craniosynostosis. CFND is inherited in a unique X-linked manner that paradoxically shows greater severity in heterozygous females than in hemizygous males. Typically, females have FND, craniofacial asymmetry, craniosynostosis, a bifid nasal tip, and grooved nails; they may also have skeletal abnormalities. In contrast, males typically show only ocular hypertelorism [Twigg et al 2004, Wieland et al 2004]. Mutations in EFNB1 or a contiguous gene deletion encompassing EFNB1 are causative [Wieland et al 2007, Apostolopoulou et al 2012]. Overlapping features of MOTA, FND, and CFND include ocular hypertelorism, a broad nasal bridge, and a bifid nasal tip. However, cranium bifidum is not observed in MOTA syndrome. Conversely, omphalocele and anorectal abnormalities are not typically found in FND sequence or CFND.Oculoauriculofrontonasal syndrome (OAFNS) is a condition with features of both oculoauriculovertebral spectrum (OAVS) and FND [Gabbett et al 2008]. Individuals typically have craniofacial dysmorphism that includes hemifacial microsomia, ear malformations, preauricular tags, epibulbar dermoids, upper eyelid colobomas, a notched or bifid nose, hypertelorism, and abnormalities of the frontal bone. Affected individuals generally have normal intelligence. The underlying genetic etiology is unknown. Omphalocele can be the result of complex etiologies including chromosomal abnormalities, environmental exposures, monogenic disorders such as Beckwith-Wiedemann syndrome [Barisic et al 2001, Cohen et al 2002, Stoll et al 2008], or malformation sequences of unknown cause such as omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex [Keppler-Noreuil 2001]. Omphalocele and ocular hypertelorism can be observed together in Donnai-Barrow syndrome (DBS) [Kantarci et al 2007], but the additional features of DBS (agenesis of the corpus callosum, sensorineural hearing loss, and diaphragmatic hernia) distinguish it from MOTA syndrome.Anteriorly placed anus and anal stenosis can be seen in a number of genetic conditions, both chromosomal and monogenic [Cho et al 2001]. In a male infant with ocular hypertelorism, FG syndrome may be considered (see MED12-Related Disorders, which includes FG syndrome type 1) [Risheg et al 2007]. However, FG syndrome and other disorders associated with anal anomalies (e.g., Townes-Brocks syndrome or VACTER [vertebral abnormalities, anal abnormalities, cardiac defects, tracheoesophageal fistula, and renal and/or radial ray abnormalities]) often have additional findings such as thumb anomalies and vertebral abnormalities that distinguish them from MOTA syndrome.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Manitoba oculotrichoanal (MOTA) syndrome, the following are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Manitoba oculotrichoanal (MOTA) syndrome, the following are recommended:Ophthalmologic evaluationSurgical evaluation of omphalocele and umbilical hernia, if present, and of anal abnormalitiesENT (ear-nose-throat) evaluation for bifid nose/notched naresPlastic surgery evaluationGenetics consultationTreatment of ManifestationsA multidisciplinary team comprising a medical geneticist, general surgeon, ophthalmologist, otolaryngologist, plastic surgeon, and social worker is preferred for optimal management of individuals with MOTA syndrome.Treatment consists primarily of surgical intervention with procedures tailored to the specific needs of the individual.Eye anomaliesColobomas of the upper eyelids and synechiae are managed conservatively with intensive ocular lubrication to avoid exposure keratopathy before surgery is performed.Anophthalmia/microphthalmia and cryptophthalmos may warrant surgical intervention and insertion of prostheses to facilitate the development of the ocular region [Seah et al 2002].Visual impairment, such as refractive errors, may be associated with colobomas and corneopalpebral synechiae.Notched or bifid nose. Rhinoplasty may be performed for cosmetic purposes.Omphalocele and umbilical hernia may be managed conservatively or by surgery. To date, all individuals with MOTA syndrome who have been managed surgically have tolerated the procedure well without procedure-related complications.Anal stenosis is generally managed by serial dilatations.Anteriorly placed anus is managed conservatively or with surgical intervention, as determined on a case-by-case basis.Psychosocial support may be indicated for the parents and the affected child.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Manitoba Oculotrichoanal Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFREM19p22.3FRAS1-related extracellular matrix protein 1FREM1 homepage - Mendelian genesFREM1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Manitoba Oculotrichoanal Syndrome (View All in OMIM) View in own window 248450MANITOBA OCULOTRICHOANAL SYNDROME; MOTA 608944FRAS1-RELATED EXTRACELLULAR MATRIX PROTEIN 1; FREM1Molecular Genetic Pathogenesis Homozygosity for an intragenic deletion of FREM1 at chromosome 9p22.3 was recently found in two separate Oji-Cree families with MOTA syndrome [Slavotinek et al 2011]. The deletion (c.824+631_c.3840-1311del) removed exons 8 to 23 of FREM1 and was consistent with loss of gene function. Homozygosity for the deletion was found in an affected brother and sister from one previously reported family [Li et al 2007] and in a severely affected male with bilateral cryptophthalmos, bilateral aberrant anterior hairlines, omphalocele, renal pelviectasis in the neonatal period, and anal stenosis. He had three affected female second cousins who were heterozygous for the same deletion that was inherited from their father; they had also inherited the same maternal allele but a mutation on the maternal allele was not identified in these patients [Slavotinek et al 2011]. Sequencing of FREM1 in other families with MOTA syndrome identified a 4-bp deletion, c.2097_2100delATTA, in a previously reported female [Fryns 2001] and the mutations c.3971T>G and c.6271G>A in another female patient [Li et al 2007, Slavotinek et al 2011]. However, in two patients with MOTA syndrome who were second cousins [Yeung et al 2009], no mutations in FREM1 were identified, suggesting genetic heterogeneity. Normal allelic variants. There are few published single nucleotide allelic variants (SNPs) in FREM1. c.5556A>G in exon 31 of FREM1 did not result in an amino acid substitution but was predicted to abolish the donor splice site for exon 31; however, this sequence variant was found in normal controls and was not considered to be pathogenic [Slavotinek et al 2011]. Pathologic allelic variants. FREM1 mutations resulting in MOTA syndrome identified to date are listed in Table 2. Note: The deletion of exons 8 to 23 found in families with MOTA syndrome affects the chondroitin sulfate proteoglycan (CSPG) domains of FREM1 [Slavotinek et al 2011].Table 2. Selected FREM1 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1) Protein Amino Acid ChangeReference SequencesNormalc.5556A>Gp.= 2NM_144966.5 NP_659403.4Pathologicc.824+631_c.3840-1311del (IVS7+631_IVS23-1311 del)p.385_1327delc.2097_2100delATTAp.Lys699Asnfs*10c.3971T>Gp.Leu1324Argc.6271G>Ap.Val2091Ilec.1945C>Tp.Arg649Trpc.2721delGp.Val908Serfs*17c.4318G>Ap.Gly1440SerSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. p.=, designates that protein has not been analyzed, but no change is expectedNormal gene product. The human FREM1 protein has a putative signal sequence, 12 chondroitin sulfate proteoglycan (CSPG) repeats, a Calx-β domain, and a C-terminal type C lectin-like domain [Alazami et al 2009]. In the mouse, Frem1 is thought to function in a ternary complex with Fras1 and Frem2 to ensure integrity of the basement membrane of the skin [Short et al 2007]. Absence of Fras1 or Frem2 causes complete loss of the ternary complex, but in mouse mutants with loss of Frem1, deposition of Fras1 and Frem2 can be unaffected or present at lower levels [Smyth et al 2004]. In the adult mouse, Frem1 is considered unnecessary for stabilization of the ternary complex. The partial redundancy of Frem1 is thought to confer greater phenotypic variability to mutants with loss of Frem1 function and to ensure a less severe phenotype than that which results from loss of Fras1 or Frem2 (Fraser syndrome), as there is some preservation of Fras1 and Frem2 function in Frem1 mutants. Abnormal gene product. All mutations reported to date in FREM1 are hypothesized to result in loss of function.