Table 1.

Genotype and Phenotypic Variability in Some Reported Cases of Raine syndrome

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