Loss-of-function variants in FREM1 have been demonstrated in Manitoba oculotrichoanal syndrome (MOTA) and bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome, but the broader phenotypic spectrum of FREM1 variants remains incompletely characterized. In this study, we report compound heterozygous variants in a prenatal case of bilateral renal agenesis. Exome sequencing revealed biallelic FREM1 variants: c.5622G>A (p.Trp1874*) and c.3274+4A>G (p.Gly1030_Ile1091del). Minigene and bioinformatic analyses confirmed that the splice site variant induces aberrant splicing and alters transcriptional expression levels. This finding underscores the crucial role of non-canonical splice site variants in FREM1 in the pathogenesis of bilateral renal agenesis. FREM1 autosomal recessive disorders include Manitoba oculotrichoanal (MOTA) syndrome, bifid nose with or without anorectal and renal anomalies (BNAR) syndrome, and isolated congenital anomalies of kidney and urinary tract (CAKUT). MOTA syndrome is characterized by an aberrant hairline (unilateral or bilateral wedge-shaped extension of the anterior hairline from the temple region to the ipsilateral eye) and anomalies of the eyes (widely spaced eyes, anophthalmia/microphthalmia and/or cryptophthalmos, colobomas of the upper eyelid, and corneopalpebral synechiae), nose (bifid or broad nasal tip), abdominal wall (omphalocele or umbilical hernia), and anus (stenosis and/or anterior displacement of the anal opening). The manifestations and degree of severity vary even among affected members of the same family. Growth and psychomotor development are normal. BNAR syndrome is characterized by a bifid or wide nasal tip, anorectal anomalies, and kidney malformations (e.g., renal agenesis, renal dysplasia). Typically, the eye manifestations of MOTA syndrome are absent. FREM1-related CAKUT has been reported in two boys from Macedonia with isolated CAKUT who had the same homozygous FREM1 pathogenic variants. The diagnosis of a FREM1 autosomal recessive disorder is established in a proband with biallelic pathogenic variants in FREM1 identified by molecular genetic testing. Treatment of manifestations: Intensive ocular lubrication to avoid exposure keratopathy before surgery is performed; release of synechiae between the eyelid and cornea; surgical intervention and/or prostheses for anophthalmia/microphthalmia and cryptophthalmos if warranted; supportive care for those with visual impairment. Rhinoplasty for notched ala nasi or bifid nose. Dilation for anal stenosis. Surgical closure of omphalocele; surgical or conservative management of umbilical hernia. Supportive treatment to preserve kidney function and electrolyte balance; dialysis and transplant if indicated in individuals with kidney failure. Psychosocial support and care coordination as needed. Surveillance: Assess kidney function in those with kidney disease with frequency per nephrologist; social work and family support at each visit. Phenotypes caused by biallelic FREM1 pathogenic variants – including MOTA syndrome, BNAR syndrome, and FREM1-related CAKUT – are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a FREM1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the FREM1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

BNAR syndrome (MIM608980) is a very rare condition: nine cases belonging to three unrelated families were reported since its first description in 2002. The distinctive clinical feature is the bifidity of the tip of the nose and its association with anorectal and/or renal anomalies. Its molecular basis consisting of biallelic FREM1 missense or nonsense mutations was elucidated after studying the original Egyptian family and was confirmed in two families originating from Afghanistan and Pakistan. We describe a fourth family originating from Turkey with signs challenging the diagnostic criteria suggested by the description of the three reported families.