Table 4 Reported FREM1 gene alterations and corresponding clinical presentation

[29]

c.4629delC + c.3971 T > G

bilateral incomplete cryptophthalmos with keratinized cornea, hypertelorism, large mouth with a small upper lip, circle-shaped whirl of hair on the left forehead, growing into the eyebrow, dysplastic ears

wide nasal bridge and tip of the nose

cutaneous syndactyly 3/4 of both hands, syndactyly 2/3 of the right foot

-

-

-

mild pyelectasis on the left kidney

\

\

[8]

∼86 kb deletion^a + c.5334 + 1G > A

\

-

mild 2–3 toe syndactyly

-

-

-

-

diaphragmatic hernia

\

[30]

c.2721delG

\

bifid nose

-

-

anorectal malformation

\

renal agenesis

-

\

c.1945C > T

\

-

-

-

-

\

renal agenesis

-

\

c.4318G > A

\

bifid nose

-

-

-

\

renal agenesis

\

airway malformation

[22]

c.2148G > T + c.3820G > T

eyelid coloboma, hypertelorism

bifid nasal tip

\

\

anterior anus, anal stenosis

\

renal pelviectasis, vaginal atresia

\

\

c.6139delG^Homozygous

corneopalpebral synechiae, eyelid coloboma, aberrant hairline, hypertelorism

bifid nasal tip

\

\

-

\

\

\

\

c.6139delG

-

bifid nasal tip

\

\

-

-

\

\

\

c.5648C > G

corneopalpebral synechiae, eyelid coloboma, aberrant hairline, hypertelorism

bifid nasal tip

\

\

-

mild delays

renal agenesis

\

\

[25]

c.3939 A > C + c.580G > A

aberrant unilateral wedge-shaped anterior hairline with the loss of ipsilateral eyebrow, hypertelorism, ipsilateral medial eyelid colobomas

bifid nose

\

\

-

\

\

\

\

[7]

homozygous 9p22.3 microdeletion in the siblings, size 30 to 52 kb encompassing several exons of FREM1

brachycephaly, bushy eyebrows, low-set posteriorly rotated and overfolded ears, teeth anomalies (diastasis of the central incisors, ab- size and shape of teeth and ab-ity of dental enamel) and short oral frenula

bifid nose

\

precocious puberty

-

mild intellectual disability

unilateral renal agenesis

\

congenital heart disease

homozygous 9p22.3 microdeletion in the siblings, size 30 to 52 kb encompassing several exons of FREM1 (NM_144966)

-

bifid nose

\

-

\

-

-

\

\

[31]

c. (? _ 1); (1393 + 1_1394-1)del

isolated midline craniosynostosis

\

\

\

\

\

\

\

[32]

c.4023C > G + c.4564G > A + c.4789G > T

craniosynostosis

\

\

\

\

\

\

\

\

c.916_936dup

craniosynostosis, papilledema

\

\

\

\

\

\

\

\

[33]

c.4705C > T

aberrant hairline, lack of eyebrows, widely-spaced eyes (42 mm), bilateral palpebral coloboma

bifid nasal tip

\

\

\

neonatal hypotrophy, generalized hypotonia, short stature

unilateral renal agenesis

\

\

[34]

c.1157A > C + c.5057C > T

hydrocephalus

-

short limbs

-

\

\

-

\

\

[27]

Del ex10-37

trigonocephaly, midface hypoplasia

short/flat

\

-

\

delay

-

\

\

Dup ex1-6; Del ex7-37

trigonocephaly, midface hypoplasia

short/flat

\

-

\

delay

-

\

\

Del

trigonocephaly, midface hypoplasia

short/flat

\

cryptorchidism

\

delay

-

inguinal hernia

pulmonary stenosis/incompetence

Del

trigonocephaly, midface hypoplasia

short

\

-

\

delay

-

inguinal hernia

peripheral pulmonary stenosis

Del

trigonocephaly, midface hypoplasia

short

\

-

\

delay

-

\

ventriculo-septal defect

c.4499A > T

trigonocephaly

\

\

\

\

delay

\

\

cardiac malformations

c.4499A > T

trigonocephaly, midface hypoplasia

broad bridge

\

-

\

-

mild right pelvicaliceal dilatation

\

\

c.1493G > A

trigonocephaly

flat nasal bridge

\

-

\

-

-

\

\