Prenatal diagnosis of Fraser syndrome caused by novel variants of FREM2

Abstract

Fraser syndrome (FS) involves multiple malformations and has a 25% recurrence risk among siblings. However, these malformations are difficult to detect prenatally, hampering prenatal diagnosis. Here, we describe a fetus with FS diagnosed using ultrasonography. Ultrasonography revealed congenital high airway obstruction syndrome and renal agenesis. Syndactyly of both hands and cryptophthalmos were noted postnatally, and the diagnosis was confirmed by genetic analysis, which showed novel compound heterozygous variants of FREM2.

Keywords: Disease genetics; Genetics.

Fig. 1. Prenatal ultrasonography images and postnatal diagnosis of a fetus with Fraser syndrome.

Bilateral renal agenesis: color Doppler image of the renal artery (a). Severe ascites (b), a hyperechogenic lung with an inverted diaphragm (c), and a distended trachea (d) were observed at 19 weeks of gestation. Fetal facial features included cryptophthalmos, hypertelorism, a small, low-set nose with a bifid tip, and microtia (e, f). Bilateral cutaneous syndactyly of the hands was also observed (g).

Fig. 2. Schematic of FREM2 protein structure and compound heterozygous FREM2 variants.

FREM2 contains chondroitin sulfate proteoglycan (CSPG) repeats and the calcium-binding loop of Na²⁺–Ca²⁺ exchange (Calx) beta domains (https://www.uniprot.org/). Electropherograms revealed biallelic variants, c.3628_3628dupA:p.(Thr1210Asnfs*8) and c.6203 T > A:p.(Leu2068*), derived from the father and mother of the patient, respectively.