Individuals with heterozygous variants in the Wnt-signalling pathway gene FZD5 delineate a phenotype characterized by isolated coloboma and variable expressivity

Figures & data

Figure 1. Schematic representation of the location of FZD5 variants reported in individuals with ocular anomalies. Variants from previous studies are in black (9–11), those from our data are indicated in red.

Figure 2. Pedigrees of the eight variants identified in the present study. Probands are indicated by an arrow, unknown genotypes are indicated by “?“.

Figure 3. Phenotypic images for individuals from families 1, 2, 5, 6, 7, and 8. (a) images of Individual 1 (Family 1 II.4) showing left microphthalmic eye and iris coloboma (top), and fundoscopy of the right eye (bottom) (b) photograph of Individual 2 (Family 2 II.1) showing bilateral microphthalmia and iris coloboma. (c) images of both eyes of Individual 5 (Family 5 II.2) showing bilateral iris colobomas. (d) photograph of Individual 6 (Family 6 II.1) showing bilateral iris colobomas. (e) images of both eyes of Individual 7 (Family 7 III.2) showing bilateral iris colobomas. (f) fundoscopy images of the father of Individual 7 (Family 7 II.2) with bilateral cavernous disc anomalies indicated by an arrow (top—right eye, bottom—left eye). (g) images of both eyes of Individual 8 (Family 8 II.1) showing bilateral iris colobomas.

Table 1. Phenotypic summary of individuals 1–8. Variants given according to NM_003468.4/NP_003459.2 and GRCh37/hg19.

Individual	1	2	3	4	5	6	7	8
FZD5 Variant	c.147delG p.(His50Thrfs *70)	c.539_540insG p.(Glu181Argfs *88)	c.541 G>T p.(Glu181*)	c. 577C>T p.(Arg193Cys)	c.1150 G>C p.(Asp384His)	c.1406T>C p.(Leu469Pro)	c.1495 G>T p.(Glu499*)	c.1566 G>A p.(Trp522*)
Coordinate	2:208,633,317	2:208,632,924	2:208,632,923	2:208,632,887	2:208,632,314	2:208,632,058	2:208,631,969	2:208,631,898
SIFT	N/A	N/A	N/A	Damaging	Damaging	Damaging	N/A	N/A
PolyPhen-2	N/A	N/A	N/A	Probably damaging	Probably damaging	Probably damaging	N/A	N/A
GnomAD MAF	Absent	Absent	Absent	0.000004164	Absent	0.000004076	Absent	Absent
Inheritance	Paternal (asymptomatic)	Maternal (left colobomatous microphthalmia and phthisis)	Maternal (myopic astigmatism, mild childhood strabismus)	Paternal (asymptomatic)	Maternal (unilateral chorioretinal coloboma)	Paternal (asymptomatic)	Paternal (bilateral cavernous disc anomalies)	Unknown
ACMG classification^a	Likely pathogenic (PVS1, PM2)	Pathogenic (PVS1, PM2, PP1)	Likely pathogenic (PVS1, PM2)	Uncertain significance (PP2, PP3)	Uncertain significance (PM2, PP1, PP2, PP3)	Uncertain significance (PP2, PP3)	Pathogenic (PVS1, PM2, PP1)	Likely pathogenic (PVS1, PM2)
Birth term	Unavailable	37 weeks	41 weeks	40 weeks	At term	39 weeks	40 weeks	Unavailable
Birth weight (kg)	Unavailable	3.06	4.21	3.09	Unavailable	3.1	3.66	3.1
Coloboma	Unilateral iris and chorioretinal; bilateral optic nerve	Bilateral iris and chorioretinal	Unilateral iris and chorioretinal	Bilateral iris	Bilateral iris and chorioretinal	Bilateral iris and chorioretinal	Bilateral iris and chorioretinal involving the disc	Bilateral iris and optic nerve
Eye (other)	Left microphthalmia. Nystagmus. L: no vision, exotropia. R: hyperopia, superior scotoma central 10°	Bilateral microphthalmia	-	-	Nystagmus, congenital cataract	Nystagmus	Nystagmus Bilateral retinal detachment surgery	Downslanted palpebral fissures, hypertelorism, upper left visual field defect
Head Circumference	-	Microcephaly (−3SD at birth, −6SD at 13 months)	+1SD (46cm [75th-91^st %] at 11 months)	42cm (2^nd %) at 9 months	55cm (+0SD)	Microcephaly (49.1 cm [0.4^th %] at 5y)	50.7cm at 8.5y (9-25^th %)	-
Neuro-development	-	Seizures	-	-	Normal	Delay	-	Some learning support at school
Cardiac	-	Atrial and ventral septal defect	-	Patent ductus arteriosus, atrial septal defect	-	-	-	-
Development	-	Severe delay	-	-	Normal	Moderate delay	-	-
Other	-	Cortical dysplasia, deafness, anal atresia, tracheo-esophageal fistula	-	Volvulus	Scoliosis	-	-	Arthritis back and knees
Additional genetic findings	-	De novo likely pathogenic SLC12A2 p.Ala327Val (NM_001046, c.980C>T)	-	-	-	De novo pathogenic DDX3X variant (NM_001193416.3, c.1171-2A>G)	arr[hg19] 1q21.1q21.2 (146497694_147825519)x1 dn, including GJA8	-

Note: - = no additional features, N/A = not applicable. All reported variants are heterozygous. ^a According to the American College of Medical Genetics and Genomics (ACMG) (23).

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17(5):405–24. doi:10.1038/gim.2015.30. PMID: 25741868.

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