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Table 1 Genotype and Phenotypic Variability in Some Reported Cases of Raine syndrome

From: A case of Raine syndrome presenting with facial dysmorphy and review of literature

Sr No. Mutation(s) in FAM20C gene Exon/ intron of mutation Pattern of mutation Sex consanguinity Fatality Origin (Ethnicity) Clinical Indications of the patients Reference
[Reference number in text]
Bone anomalies facial dysmorphic appearance orodental abnormalities Developmental delay
1 c.1603C >T (p.Arg535Trp) Exon 10 Homozygous missense mutation M Yes neonatal death Caucasian Periosteal bone formation, Osteosclerosis, Thoracic Hypoplasia, brachycephaly with very large anterior and posterior fontanelles, prenatal fractures of both clavicles and some ribs Prominent forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge, exophthalmos, hypoplastic nose with choanal atresia, high arched palate with mid-line groove but no cleft, hyperplastic nodular gums, low set ears, small jaw Not Reported Not Reported Kingston et al., 1991 [9]
Simpson et al., 2007 [21]
2 c.915-3C>G Intron 4/Exon 5 acceptor splice-site change Homozygous splice site mutation M No neonatal death Arab Periosteal bone formation, Osteosclerosis, Thoracic Hypoplasia, and marked bowing of the femurs, tibiae, ulnae, short limbs Prominent forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge, wide anterior fontanelle, exophthalmos, bilateral choanal atresia, large protruding tongue Not Reported Not Reported Al-Gazali et al., 2003 [24]
Simpson et al., 2007 [21]
3 c.1121T>G (p.Leu374Arg) Exon 6 Homozygous missense mutation F Yes neonatal death Turkish Periosteal bone formation, Osteosclerosis, Thoracic Hypoplasia, Pulmonary Hypoplasia, hypoplastic fingernails, Brachydactyly, metaphyseal flaring, narrow medula Bi-temporally narrowed forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge, carp-shaped mouth with narrow lips, large low set ears, posteriorly rotated ears, smooth and prominent philtrum Gingival hyperplasia Diffused intracerebral Calcifications, microcephaly Hulskamp et al., 2003 [14]
Simpson et al., 2007 [21]
4 45, XY psudic (7;7) (p22;p22) NA Chromosome 7 rearrangement and micro deletion. FAM20C gene is located within the deleted region M No neonatal death
(died 2 h after birth)
Unknown Lethal osteosclerotic bone dysplasia, irregular periosteal bone formation along the clavicles and ribs, skull had wide cranial sutures with evidence of premature closure, base of the skull showed an increased thickness of all bony landmarks, pulmonary Hypoplasia, Thoracic Hypoplasia Prominent forehead, short neck, proptosis, midfacial hypoplasia, and a depressed nasal bridge Not Reported Not Reported Simpson et al., 2007 [21]
5 c.1093G>A (p.Gly365Arg) Exon 6 Homozygous M Yes neonatal death Unknown Periosteal bone formation, Osteosclerosis, Thoracic Hypoplasia, Pulmonary Hypoplasia Prominent forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge Not Reported Not Reported Simpson et al., 2007 [21]
6 c.1094G>A (p.Gly365Glu) Exon 6 Compound heterozygous mutation F No neonatal death Unknown Periosteal bone formation, Osteosclerosis Prominent forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge Unknown Cerebral Calcifications Simpson et al., 2007 [21]
7 c.1322-2A>G Intron 7 /Exon 8 Intron 7/Exon 8 acceptor splice-site mutation
8 c.914+5G>C Exon 4 /Intron 4 Exon 4/Intron 4 donor splice site mutation F No neonatal death Unknown Periosteal bone formation, Osteosclerosis, Thoracic Hypoplasia, Pulmonary Hypoplasia Prominent forehead, short neck, proptosis, midfacial hypoplasia, depressed nasal bridge Unknown Cerebral Calcifications Simpson et al., 2007 [21]
9 c.1404-1G>A Intron 8 /Exon 9 Intron 8/Exon 9 acceptor splice site mutation
10 c.1309G>A (p.Asp437Asn) Exon 7 Homozygous missense mutation M Yes (Age 8 years at the time of inverstigation)
The details of death is unavailable
Unknown Sclerosing bone dysplasia, metaphyseal sclerosis of the long bones, diffuse abnormalities of the skull, thickening and coarse trabeculation, prominent mastoid bulges, short stature Brachycephaly, downslanted eyes, hypoplastic nose, small downturned mouth, proptosis, turribrachycephaly, plagiocephaly, downslanting palpebral fissures, proptosis, depressed nasal bridge, small nose, protruding tongue, thick alveolar margins, low-set ears High palate, abnormal teeth Hydrocephalus, impaired early development, with an increase in age severe developmental delay observed Simpson et al., 2009 [11]
11 c.796G>A (p.Gly266Arg) Exon 2 Compound Heterozygous missense mutation M No (Age 11 years at the time of inverstigation). The details of death is unavailable Unknown Sclerosing bone dysplasia, pectus excavatum, bulbous fingertips, thick fingers, large halluces, short stature Turribrachycephaly, hypertelorism, arched eyebrows, an inferiorly placed right eye, low-set and protuberant ears, flat nasal bridge with rounded and bulbous nasal tip and prominent alae nasi, sunken midface, wide mouth with large tongue, relative prognathism Secondarily edentulous Hydrocephalus, impaired early development, with an increase in age severe developmental delay observed Simpson et al., 2009 [11]
12 c.796G>A (p.Gly266Arg) Exon 3           
13 c.1630C>T (p.Arg544Trp) Exon 10 Homozygous missense mutation M Yes died 38 days after birth Indian subcontinent Wide metaphysic, cortical hyperostosis, Osteosclerosis, bowed femur, narrow thorax Cleft palate, long philtrum, open mouth appearance, midfacial hypoplasia, flat face, depressed nasal bridge, small nose, choanal atresia, entropion of eyelids, proptosis, low set ears, prominent forehead, clover leaf skull Hypoplastic maxilla (excluding the molar region), small mandible/ micrognathia, Microcephaly Kochar et al., 2010 [20]
14 c.940C>T (p.Pro314Ser)
(two siblings; Case 1 and Case 2)
Exon 4 Homozygous missense mutation F (n = 2) yes (Age 1 year and 4 years at the time of investigation)
The details of death is unavailable
Algerian Case 1: Osteosclerosis
Case 2: cerebral calcifications within parieto-occipital and periventricular white matter, increased density of vertebral bodies and calcifications of several intervertebral disks, presence of chain-like calcifications
Case 1: High forehead, hypertelorism with bilateral epicanthal folds and slightly downslanting palpebral fissures, nasal root hypoplasia, anteverted nares, dysplastic and posteriorly angulated ears with prominent lobule.
Case 2: brachycephaly, bilateral epicanthal folds, midface and nasal root hypoplasia with absence of nasal crest and micrognathia.
High palate, small teeth with enamel dysplasia. Normal psychomotor development at the time of investigation Fradin et al., 2011 [13]
15 c.803C>T (p.Thr268Met) Exon 3 Compound heterozygous missense mutation M (n = 2) No (Age 18 years at the time of investigation). The details of death is unavailable Norway Osteosclerosis, short distal phalanges Dolicocephaly, a narrow face with a narrow malar region, prominent forehead, depressed nasal bridge, low set eyes, hypotelorism, prognathism, a high arched palate with a midline ridge, small mouth, flat malar area Tooth decay (evident by approximately 18 months of age) periapical abscesses. enlarged pulp chambers, elongated pulp horns up to the enamel-dentin junction, globular defects in the dentine, gingival hyperplasia Slightly delayed language and fine motor skills at age 11 years. Rafaelsen et al., 2013
[28]
16 c.915C>A (p.Y305X) Exon 4 Age 16 years at the time of investigation). The details of death is unavailable
17 46,XY.arr[hg19] 7p22.3 (36480-523731) chromosome 7p22.3 Homozygous
Complex rearrangement of chromosome and deletion of 487-kb at chromosomal location 7p22.3 that contains FAM20C gene
Unknown Unknown The details of death is unavailable Unknown Diffuse osteosclerosis, appositional new bone formation, the obliteration of the medullary cavities, narrow thorax, pseudo-rib fractures, small distal phalanges Prominent forehead, eye proptosis, severe depression of the nasal bridge with short upturned nose, midface hypoplasia, micrognathia,  protruding tongue, Unknown Unknown Ababneh et al., 2013 [43]
18 c.1222C>T
(p.Arg408Trp)
Exon 6 Homozygous mutation M Yes (Age 61years at the time of investigation). The details of death is unavailable Japanese Hypophosphatemic osteomalacia, periosteal bone formation in the long bones, bone mineral density in the femoral neck, ossification of the posterior longitudinal ligament Not reported Worn out teeth, dental demineralization, loss of all teeth by the age of 17 years Not reported Takeyari et al., 2014 [29]
19 c.784+ 5G>C*
(p.Trp202Cysfs*37)
(three siblings)
After Exon 2 Homozygous donor splice site mutation F (n = 1)
M (n = 2)
Yes (Age 21 years; 22 years and 27 years at the time of investigation). The details of death is unavailable Brazilian Case 2: Short fingers Case 1,2,3: Dysplastic ears, midface hypoplasia, exophthalmos, Case 1,2,3: Dental caries, calculus, severe gingivitis, dental plaque, open bite malocclusion, abnormal enamel, high arched and narrow palate, micrognathia, periapical abscesses, yellow brownish discoloration of teeth Case 1: Intracranial calcifications,
Case 2: microcephaly,
Case 3: microcephaly,
Acevedo et al., 2015 [8]
20 c.1487C>T (p.Pro496Leu)
(two siblings)
Exon 9 Homozygous missense mutation M (n = 2) Yes (Age 13 years and 12 years at the time of investigation).
The details of death is unavailable
Brazilian Case1,2: small hands with bulbous fingertips and clinodactyly of the fifth fingers, under-mineralized distal phalanges, shaft and growth plate under-mineralization, bowing of the radius bones Case 1,2: choanal atresia, low set ears, a hypoplastic nose with depressed nasal bridge, prominent alae nasae, down-slanting palpebral fissures and exophthalmos Case 1,2: midface hypoplasia, micrognathia, high arched and narrow palate, enlarged gingival and palatal mucosa, unerupted permanent teeth, hypoplastic AI. recurrent periapical dental abscesses Case 1,2: delay in psychomotor development, microcephaly Acevedo et al., 2015 [8]
21 c.1228T>A (p.Ser410Thr) Exon 6 Homozygous missense mutation unknown unknown The details of death is unavailable Unknown unknown unknown unknown Unknown Emory Genetics Laboratory; 2016
[47]
22 c.676T > A
(p.Trp226Arg)
Exon 2 Homozygous missense mutation F (n = 2)
M (n = 1)
Yes The details of death is unavailable Moroccan Not Reported Not Reported amelogenesis imperfecta learning disability, seizures Elalaoui et al., 2016 [30]
23 c.1135G>A (p.Gly379Arg) Exon 6 Homozygous missense mutation M Yes The details of death is unavailable South East Asian Osteosclerosis, widening of the metaphyses of the long bones, thick and short ribs, fracture of the mid-shaft of the left clavicle, bowing of long bones, bilateralperiventricular and parenchymal punctate calcifications Choanal atresia, frontal bossing, proptosis, mid-face hypoplasia with a depressed nasal bridge, bulbous nasal tip, tented upper lip Not Reported Abnormal/dystonic movements, hypertonia, hyper reflexia Mahmood et al., 2017 [7]
24 c.1228T>A (p.Ser410Thr) Exon 6 Homozygous missense mutation F Yes Age 6 years the time of investigation). The details of death is unavailable Indian Osteosclerosis, hallux valgus, sandal gap deformity, clinodactyly of toes, pes planus Flat forehead, epicanthal folds, hypertelorism, depressed and low nasal bridge with bulbous nasal tip, flaring nares, prominent philtrum, pointed chin. No orodental anomalies were observed. psychomotor developmental delay Present case