The faciooculoacousticorenal (FOAR) syndrome was first described as comprising facial anomalies, ocular anomalies, sensorineural hearing loss, and proteinuria. Facial features include prominent brow, short nose, and hypertelorism, and ocular anomalies include myopia, iris hypoplasia, and/or retinal detachment (Regenbogen ... The faciooculoacousticorenal (FOAR) syndrome was first described as comprising facial anomalies, ocular anomalies, sensorineural hearing loss, and proteinuria. Facial features include prominent brow, short nose, and hypertelorism, and ocular anomalies include myopia, iris hypoplasia, and/or retinal detachment (Regenbogen and Coscas, 1985). Donnai-Barrow syndrome (DBS) was first described as a distinct disorder characterized by diaphragmatic hernia, exomphalos, absent corpus callosum, myopia, and sensorineural deafness. The classic distinguishing features between the 2 disorders were presence of proteinuria and absence of diaphragmatic hernia and corpus callosum anomalies in FOAR (Donnai and Barrow, 1993). However, early reports noted that the 2 disorders shared many phenotypic features and may be identical (e.g., Devriendt et al., 1998). Although there is variability in the expression of some features (e.g., agenesis of the corpus callosum and proteinuria), the disorders are now considered to represent the same entity (Kantarci et al., 2007).
Murdoch and Mengel (1971), Holmes and Schepens (1972), and Ozer (1974) independently reported a brother and sister with a syndrome of ocular and facial anomalies, telecanthus, perceptive deafness, epiphyseal dysplasia of the femoral heads, and proteinuria. Myopia and ... Murdoch and Mengel (1971), Holmes and Schepens (1972), and Ozer (1974) independently reported a brother and sister with a syndrome of ocular and facial anomalies, telecanthus, perceptive deafness, epiphyseal dysplasia of the femoral heads, and proteinuria. Myopia and both telecanthus and true hypertelorism were present. Fraser (1976) described a single case with proteinuria. Donnai and Barrow (1993) described 2 unrelated patients, a male and a female, with a syndrome of diaphragmatic hernia, exomphalos, hypertelorism, agenesis of the corpus callosum, severe sensorineural deafness, and severe myopia. One child had iris coloboma and retinal detachment. Monitoring of subsequent pregnancies in both families revealed a further affected fetus in each. In a note added in proof, Donnai and Barrow (1993) indicated that a third affected child, a female in a possibly related family, had been identified. The authors suggested autosomal recessive inheritance. Gripp et al. (1997) described a male infant, the offspring of first-cousin parents from Saudi Arabia, who had wide anterior fontanel and metopic suture with frontal bossing, hypertelorism, downslanting palpebral fissures, bilateral iris coloboma, omphalocele, and bilateral absence of the diaphragm with herniation of internal organs causing pulmonary hypoplasia and death. Autopsy also showed intestinal malrotation. The findings were considered consistent with the syndrome described by Donnai and Barrow (1993). Schowalter et al. (1997) reported an 11-year-old boy with FOAR syndrome. He had iris coloboma, iris hypoplasia, macular hypoplasia, cataract, high myopia, retinal detachment, moderate sensorineural hearing loss, and proteinuria without aminoaciduria. Facial features included prominent brow, flat nasal bridge, hypertelorism, and downslanting palpebral fissures. In contrast to the previously reported patients, he had normal intellect and was learning Braille. Devriendt et al. (1998) reported a male infant with hypertelorism, severe myopia, sensorineural deafness, diaphragmatic hernia, and proteinuria. Other features included large anterior fontanel, depressed nasal bridge, downslanting palpebral fissures, and delayed development. The proteinuria was nonselective and did not include glucose or amino acids. Although the child did not have agenesis of the corpus callosum or exomphalos, the authors concluded that FOAR and Donnai-Barrow syndrome are the same entity. Devriendt et al. (1998) postulated that the brothers reported by Ohlsson (1963) may have had the same syndrome. Avunduk et al. (2000) reported a male child, born of consanguineous parents, who had exomphalos, agenesis of the corpus callosum, right iris coloboma, high myopia, retinal anomalies, and sensorineural deafness. Facial features included prominent forehead, long nose, downslanting palpebral fissures, and hypertelorism. There was no evidence of diaphragmatic hernia or heart defects. The authors noted the striking similarities to the patients reported by Donnai and Barrow (1993). The report confirmed autosomal recessive inheritance. Chassaing et al. (2003) reported Donnai-Barrow syndrome in 2 sets of sibs and in an unrelated child, with features including diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness. Kantarci et al. (2007) reported follow-up of 1 affected girl reported by Chassaing et al. (2003). At age 6 years, she was legally blind with mild developmental delay, but was learning Braille. She had a nonacidotic proximal tubulopathy. Kantarci et al. (2007) reported a large consanguineous family from the United Arab Emirates in which 5 sibs had Donnai-Barrow syndrome. The proband had characteristic cranial features and died of complications of congenital diaphragmatic hernia. Four surviving sibs had variable clinical features, including diaphragmatic eventration with pulmonary hypoplasia, omphalocele, sensorineural deafness, agenesis of the corpus callosum, hypertelorism, high myopia, large anterior fontanel, and developmental delay. One child also had retinal dystrophy, scoliosis, rib and vertebral anomalies, and short sternum. Imaging of 1 child showed numerous brain anomalies, including partially empty sella turcica, small pons, periventricular nodular heterotopia, small optic nerves and chiasm, ocular colobomas, and malformation of the left horizontal semicircular canal and vestibule. Urine samples from affected individuals showed proteinuria with spillage of retinol-binding proteins (see RBP1, 180260) and vitamin D-binding proteins (see DBP, 139200).
In 4 affected sibs with Donnai-Barrow syndrome from the United Arab Emirates, Kantarci et al. (2007) identified a homozygous mutation in the LRP2 gene (600073.0001). Kantarci et al. (2007) also identified pathogenic mutations in the LRP2 gene in ... In 4 affected sibs with Donnai-Barrow syndrome from the United Arab Emirates, Kantarci et al. (2007) identified a homozygous mutation in the LRP2 gene (600073.0001). Kantarci et al. (2007) also identified pathogenic mutations in the LRP2 gene in affected individuals reported by Donnai and Barrow (1993) (600073.0004-600073.0006) and Chassaing et al. (2003) (see, e.g., 600073.0002-600073.0003). Kantarci et al. (2007) identified mutations in the LRP2 gene (600073.0007; 600073.0008) in a Belgian child reported by Devriendt et al. (1998) as having faciooculoacousticorenal syndrome. The findings confirmed that FOAR and Donnai-Barrow syndrome are the same entity.
The diagnosis of Donnai-Barrow syndrome (DBS) is based on the recognition of characteristic clinical features combined with a distinctive pattern of low-molecular-weight proteinuria. It is confirmed by detection of mutations in LRP2, which codes for the protein low-density lipoprotein receptor-related protein 2 precursor (megalin)....
DiagnosisClinical DiagnosisThe diagnosis of Donnai-Barrow syndrome (DBS) is based on the recognition of characteristic clinical features combined with a distinctive pattern of low-molecular-weight proteinuria. It is confirmed by detection of mutations in LRP2, which codes for the protein low-density lipoprotein receptor-related protein 2 precursor (megalin).No single feature is pathognomonic for DBS, nor have diagnostic criteria been formalized. However, the diagnosis should be entertained when several of the following structural and functional anomalies are present:Craniofacial. Marked ocular hypertelorism, large anterior fontanelle, wide metopic suture, widow’s peak in anterior hairline, depressed nasal bridge, short nose, and posterior rotation of the ears are present in nearly 100% of affected individuals. The facial appearance, although not coarse, is characteristic (see Figure 1).FigureFigure 1. Face: same male with Donnai-Barrow syndrome over time A. At age six months; broad forehead prominent ocular hypertelorism, left iris coloboma, and short nose B. At age 2.5 years; same features are apparent. (more...)Ocular. Enlarged globes (leading to the appearance of prominent eyes) and downslanting palpebral fissures are found in all affected individuals. Iris coloboma is observed in a minority of patients. High myopia (>6 diopters), retinal detachment, retinal dystrophy, and progressive visual loss are observed.Sensorineural hearing loss is a universal finding.Diaphragmatic hernia (or eventration) and/or omphalocele (or umbilical hernia) are each reported in approximately 50% of affected individuals. The two defects occur together in approximately one third of cases. Note: The absence of either or both does not exclude the diagnosis.Neurologic. Either complete or partial agenesis of corpus callosum (ACC) is reported in almost all individuals clinically diagnosed with DBS (see Figure 2). Interestingly, ACC was not observed in any individuals with the clinical diagnosis of faciooculoacousticorenal (FOAR) syndrome (including the LRP2 mutation-confirmed case reported by Devriendt et al [1998] with overlapping DBS/FOAR features). FigureFigure 2. MRI in a three-year-old female demonstrates numerous abnormalities including hypogenesis of the corpus callosum (most notably involving the rostrum and splenium) (long white arrow), partially empty sella turcica (S), and small pons (P). Note: FOAR syndrome, or faciooculoacousticorenal syndrome, is now recognized to be allelic to DBS.Developmental delay is almost always present.TestingAbsent or abnormally functioning megalin, the protein encoded by LRP2, prevents normal renal proximal tubule reuptake of megalin ligands, resulting in excess spillage of low-molecular-weight proteins in the urine in 100% of individuals with DBS.Two important low-molecular-weight proteins identified by urinary protein electrophoresis:Retinol-binding protein (RBP)Vitamin D-binding protein (DBP)Note: Limited data suggest that excess urinary spillage of these moieties may result in diminished serum concentrations of vitamin A (retinol) and vitamin D.Note: The use of a “dipstick” (which identifies albumin) to assess urinary protein is not an adequate substitute for urinary protein electrophoresis because individuals with DBS spill protein moieties with molecular weights lower than that of albumin.Molecular Genetic TestingGene. LRP2 (low-density lipoprotein receptor-related protein 2) is the only gene currently known to be associated with DBS.Clinical and research testingSequence analysis has identified 12 LRP2 missense, nonsense, splice junction, or frameshift mutations in eight families [Kantarci et al 2007, Kantarci et al 2008] (see Table 2). Table 1. Summary of Molecular Genetic Testing Used in Donnai-Barrow SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityLRP2Sequence analysisSequence variants 2, 3100%Clinical1. 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. Kantarci et al [2007], Kantarci et al [2008]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 StrategyTo confirm/establish the diagnosis in a proband with clinical characteristics of DBS:Brain MRI scan for identification of partial or complete agenesis of corpus callosumUrinary protein electrophoresis to identify low molecular-weight proteins and characteristic banding pattern.LRP2 sequence analysis Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. However, urine collected from several proven heterozygotes demonstrated higher-than-normal total protein [Kantarci et al 2007].Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.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) DisordersDBS [Donnai & Barrow 1993] and FOAR syndrome [Holmes & Schepens 1972, Schowalter et al 1997] were reported as two distinct entities, although overlapping clinical features were appreciated [Devriendt et al 1998, Chassaing et al 2003]. It is now known that these syndromes represent the same clinical entity and are caused by mutations in LRP2 [Kantarci et al 2007].No phenotypes other than DBS/FOAR syndrome are currently known to be associated with mutations in LRP2.
Information on long-term follow-up and natural history of Donnai-Barrow syndrome (DBS) is limited to a few individuals because many affected pregnancies are interrupted or result in perinatal death secondary to congenital malformations. The following information is based on the citations Holmes & Schepens [1972], Donnai & Barrow [1993], Schowalter et al [1997], Devriendt et al [1998], Avunduk et al [2000], Chassaing et al [2003], Chen [2007], Kantarci et al [2007], and Patel et al [2007], and reviewed in Pober et al [2009] unless otherwise indicated....
Natural HistoryInformation on long-term follow-up and natural history of Donnai-Barrow syndrome (DBS) is limited to a few individuals because many affected pregnancies are interrupted or result in perinatal death secondary to congenital malformations. The following information is based on the citations Holmes & Schepens [1972], Donnai & Barrow [1993], Schowalter et al [1997], Devriendt et al [1998], Avunduk et al [2000], Chassaing et al [2003], Chen [2007], Kantarci et al [2007], and Patel et al [2007], and reviewed in Pober et al [2009] unless otherwise indicated.Relatively high birth weight (~4 kg) has been recorded in several cases. Urgent surgical treatment of diaphragmatic hernia and/or omphalocele in newborns with these complications and postoperative care dominates the early weeks.Progressive visual loss resulting in legal blindness is common and seemingly the result of severe myopia and an attendant risk for retinal detachment, although prompt treatment can improve the chances of useful vision. Prophylactic treatment with peripheral barrier photocoagulation to prevent retinal detachment has been successful in several cases. Progressive retinal dystrophy has been observed in a few individuals; the exact nature and rate of progression of the retinal dystrophy remain to be determined. Sensorineural hearing loss is universal. Some individuals have useful hearing with hearing aids and a few have received cochlear implants. However, two long-term survivors (ages 15 and 21 years) have profound hearing loss (see Deafness and Hereditary Hearing Loss Overview for definitions).Motor milestones are only slightly delayed and most children become continent.No formal studies of intellectual functioning exist, but available data suggest that all individuals with DBS have intellectual disabilities of varying degrees ranging from mild to moderate. Formal assessment is difficult because of the severe vision and hearing deficits. The oldest individual known to have DBS is age 21 years and attends a college with special provision for his hearing and vision problems. He has no speech but communicates using British Sign Language. He can dress himself and do tasks such as keep his room tidy, make his bed, and operate a microwave and a DVD player. He takes part in supported employment and enjoys mailing and labeling tasks. He enjoys social activities and going to restaurants although he still requires some assistance with cutting food. The presence of additional brain anomalies, such as periventricular nodular heterotopia and abnormalities of gyral patterns, is increasingly appreciated.Involvement of other organ systems (e.g., ventriculoseptal defect [VSD] in the cardiovascular system and bicornuate uterus in the genitourinary system) has been reported but is rare. The prevalence of such defects may be under-estimated because of limited examination of fetuses with DBS and of affected infants who died in the neonatal period. One individual with focal segmental glomerulosclerosis has been reported; whether this finding is coincidental or a rare manifestation of DBS is presently unknown [Shaheen et al 2010].General health in childhood and adolescence is good although several individuals have developed a seizure disorder in adolescence.Pubertal development occurs at the appropriate times. Height and weight appear to be within the normal range; two of the older children are tall, with heights on the 90th centile.Pathophysiology. Megalin has many ligands. Because individuals with DBS have absent or dysfunctional megalin, it seems likely that failure of renal reabsorption of compounds such as retinol or vitamin D could lead to serum and/or cellular deficiencies. Preliminary data from several affected individuals confirms decreased concentration of circulating retinol compared to controls [Kantarci et al 2007]. Megalin also localizes to the human brain and may be a key component in the transport of ligands across the choroid plexus and into astrocytes for neuronal development during embryogenesis. Failure of these processes may result in observed brain malformations and intellectual disabilities [Bento-Abreu et al 2008].Evidence further suggests that dysregulation of cell growth and intraocular fluid production in the setting of megalin deficiency is the likely cause of the enlarged ocular globes and high myopia [Veth et al 2011].
Currently, the phenotype cannot be predicted by the genotype. The explanation for the presence of intrafamilial phenotypic variation, which can be considerable among family members with the same genotype, is unknown [Kantarci et al 2007]....
Genotype-Phenotype CorrelationsCurrently, the phenotype cannot be predicted by the genotype. The explanation for the presence of intrafamilial phenotypic variation, which can be considerable among family members with the same genotype, is unknown [Kantarci et al 2007].
Donnai-Barrow syndrome (DBS) is associated with congenital diaphragmatic hernia (CDH) (see Congenital Diaphragmatic Hernia Overview)....
Differential DiagnosisDonnai-Barrow syndrome (DBS) is associated with congenital diaphragmatic hernia (CDH) (see Congenital Diaphragmatic Hernia Overview).The following syndromes include some features of DBS:Pallister-Killian syndrome (12p tetrasomy mosaicism) [OMIM 601803]. Affected infants can have diaphragmatic hernia and relatively high birth weight as well as ocular hypertelorism plus a range of other structural and developmental defects.Fryns syndrome comprises diaphragmatic defects, pulmonary hypoplasia, characteristic facial appearance including coarse face, and distal digital hypoplasia. A variety of other anomalies involving brain, cardiovascular system, and genitourinary system have been reported. No genetic mutation responsible for Fryns syndrome has been identified. In fact, Fryns syndrome may be etiologically heterogeneous, as some cases are seemingly autosomal recessive whereas others are caused by de novo microdeletions.Chudley-McCullough syndrome [OMIM 604213] is a rare autosomal recessive disorder with characteristic features of sensorineural hearing loss, partial agenesis of the corpus callosum, arachnoid cysts, and hydrocephalus.Acrocallosal syndrome [OMIM 200990] is an autosomal recessive disorder associated with macrocephaly, ocular hypertelorism, postaxial polydactyly, hallux duplication, and absence of the corpus callosum.Dent disease 1, Dent disease 2, andLowe syndrome. Affected individuals may display low molecular-weight proteinuria. Males with Lowe syndrome have a combination of bilateral dense congenital cataracts, infantile congenital hypotonia, delayed development, and proximal renal tubular transport dysfunction of the Fanconi type. Craniofrontonasal syndrome [OMIM 304110], an X-linked condition resulting from EFNB1 mutations, is characterized by agenesis of the corpus callosum, congenital diaphragmatic hernia, umbilical hernia, hypertelorism, and frontal bossing. 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 Donnai-Barrow syndrome (DBS), the following studies are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Donnai-Barrow syndrome (DBS), the following studies are recommended:Neuroimaging (preferably MRI scan)Detailed ophthalmologic examination including glaucoma screeningAudiologic evaluationQuantitative urine protein determinationSerum tests of renal function including blood urea nitrogen (BUN) and serum creatinine concentrations Determination of circulating levels of vitamin A, vitamin D, and other regulators of calcium statusEEG if symptoms suggest a seizure disorderGenetics consultationTreatment of ManifestationsThe following are appropriate:Surgical repair of diaphragmatic hernia and postoperative assessment of respiratory function to determine if the risk for long-term respiratory problems is increasedSurgical repair of omphalocele Note: Surgical repair of omphalocele and/or diaphragmatic hernia seems to pose no greater risk than repair of these defects in children with other genetic syndromes.Provision of corrective lenses for myopia; treatment of retinal detachments or glaucomaProvision of appropriate hearing aids and/or cochlear implants (see Deafness and Hereditary Hearing Loss Overview for more details)Education tailored to degree of intellectual, visual, and hearing disabilitiesAntiepileptic drugs for seizuresSurveillanceFormal ophthalmic examination should be performed as soon as the diagnosis of DBS is considered. Frequent and serial monitoring is needed; the schedule should be determined by the findings present. Treatments (e.g., peripheral laser photocoagulation) may minimize the risk of retinal detachment resulting from high myopia.Hearing evaluations should be performed as soon as the diagnosis of DBS is considered. Data on the natural history and possible progression of hearing loss are not currently available and thus no timetable for monitoring has been established.Periodic monitoring of renal function seems prudent, based on the report of Shaheen et al [2010]. However the frequency of DBS-associated renal dysfunction is not currently known. 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. Donnai-Barrow Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDLRP22q31.1Low-density lipoprotein receptor-related protein 2LRP2 homepage - Mendelian genesLRP2Data 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 Donnai-Barrow Syndrome (View All in OMIM) View in own window 222448DONNAI-BARROW SYNDROME 600073LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 2; LRP2Molecular Genetic PathogenesisDonnai-Barrow syndrome (DBS) is caused by presumed loss-of-function mutations in the low-density lipoprotein receptor-related protein 2 gene (LRP2) encoding an endocytic transmembrane glycoprotein, megalin (LRP-2/gp330) [Kantarci et al 2007]. Megalin was first described as the pathogenic autoantigen of Heymann nephritis in rats. Most of the megalin-knockout mice (megalin -/-) die shortly after birth from respiratory insufficiency [Willnow et al 1996, Leheste et al 1999].Examination of megalin-deficient mice shows forebrain anomalies including ACC and mild holoprosencephaly [Willnow et al 1996, Leheste et al 1999]. Among the few persons with DBS with detailed neuroimaging, callosal abnormalities and ocular globe abnormalities are universal, but none has shown evidence of holoprosencephaly. Periventricular nodular heterotopia and cortical patterning abnormalities in one affected individual underscore the important role of megalin in early human brain development [Kantarci et al 2007].Megalin is not necessary in kidney development, but is required for endocytotic processes [Willnow et al 1996, Leheste et al 1999, Anzenberger et al 2006, Fisher & Howie 2006]. Megalin-deficient mice excrete low-molecular-weight plasma proteins including DBP and RBP, α1-microglobulin and odorant-binding protein in the urine [Leheste et al 1999]. Similar to megalin-deficient mice, all affected individuals with DBS and confirmed LRP2 mutations demonstrate low-molecular-weight proteinuria with increased excretion of DBP and RBP [Kantarci et al 2007].Normal allelic variants. LRP2 spans approximately 236 kb of genomic DNA and contains 79 coding exons. The first half of exon 1 and the latter portion of exon 79 are untranslated [Hjälm et al 1996].Pathologic allelic variants. Twelve mutations have been documented in eight affected kindreds [Kantarci et al 2007, Kantarci et al 2008]. Each kindred has unique mutations distributed throughout the gene. The homozygous or compound heterozygous LRP2 mutations found in affected individuals have been small deletions or insertions, or conserved splice-site, nonsense, and missense mutations inherited from each heterozygous carrier parent. As a rare event, one affected individual was homozygous for an LRP2 mutation resulting from paternal isodisomy of chromosome 2. Specifically, the father is a heterozygous carrier of the mutation, whereas the mother has two normal LRP2 alleles [Kantarci et al 2008].Table 2. Selected LRP2 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1) Protein Amino Acid Change (Alias 1) Reference Sequencesc.770-2A>G (IVS7-2A>G)--NM_004525.2 NP_004516.2c.1093C>Tp.Arg365*c.1341+2T>G (IVS11+2T>G)--c.2840-1G>A (IVS18-1G>A)--c.7564T>Cp.Tyr2522Hisc.8452+1G>A (IVS44+1G>A)--c.8516_8519delTTTAp.Tyr2840Cysfs*67 (Val2839Valfs*67)c.9358_9359delAGp.Ser3120Trypfs*26c.9484_9485delGTp.Val3162Leufs*2c.10195C>Tp.Arg3399*c.11469_11472delTTTG 2p.Cys3823Trpfs*159c.13139dupC (13139insC)p.Cys4381Metfs*12 (Pro4380Profs*12)See 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. The homozygous mutation caused by paternal uniparental isodisomy for chromosome 2 in an affected individual with DBS/FOAR [Kantarci et al 2008]Normal gene product. The 600-kd megalin protein comprises 4655 amino acids. Megalin is a member of the low-density lipoprotein (LDL) receptor gene family, which is expressed predominantly in apical surface of absorptive or secretory epithelia. The large extracellular domain of the protein contains 36 cysteine-rich LDL-receptor class A (complement type) motifs, 37 LDL-receptor class B (YWTD-containing) motifs, and 17 EGF-like repeats. The single transmembrane domain of the protein is followed by a short cytoplasmic (C-terminal) domain containing two NpxY motifs. A variety of tissues including the brain, eye, renal proximal tubule, lung, intestine, uterus, oviduct, male reproductive tract, and embryonic yolk sac express megalin. Megalin binds more than 50 ligands, including lipoproteins, vitamin-binding proteins, hormones, enzymes, and immune- and stress-response-related proteins. It has been proposed that megalin interacts with the sonic hedgehog protein. Receptor-associated protein and megalin are coexpressed in different tissues during development. Megalin and a membrane receptor cubilin (gp280) share many ligands [Fisher & Howie 2006].Abnormal gene product. The mutations in LRP2 that cause DBS are predicted to result in loss of function of the protein based on observation of similar phenotypes among all affected individuals, including those with homozygous frameshift mutations causing premature termination codons. No detailed description or explanation of the pathophysiology of the mutant protein in causing the human congenital malformations characteristic of DBS is available.