Whole-Exome Sequencing Reveals FAT4 Mutations in a Clinically Unrecognizable Patient with Syndromic CAKUT: A Case Report

Abstract

We present the case of a patient of Macedonian origin with unilateral renal agenesis and ureterovesical junction obstruction in combination with further abnormalities including midface hypoplasia, scoliosis as well as camptodactyly of one toe. Whole-exome sequencing analysis revealed compound heterozygous variants in the FAT4 gene. Recessive variants in FAT4 are a known cause of van Maldergem syndrome (VMS) in which congenital anomalies of the kidney and urinary tract are a less characteristic but common feature. The initial presentation of our patient was not clinically recognizable. However, in view of the molecular findings, the most likely diagnosis is a mild manifestation of VMS. Only very few publications have reported patients with VMS and mutations in FAT4 to date. With this case, we hope to provide further insight into the phenotypic variability of this syndrome.

Monogenic causes of chronic kidney disease in adults

“…21 As demonstrated in our cohort, mild extrarenal features commonly go unrecognized until clinical re-review is performed in full cognizance of the molecular genetic diagnosis (Table 2; Supplementary Table S1). 22 This strategy of "reverse phenotyping" has been described extensively for childhood cohorts, 23 and our data show that this finding holds relevance for adults who have CKD. Identification of specific pathogenic mutations can also facilitate screening for otherwise undetected extrarenal features.…”

Emerging Mechanisms of Growth and Patterning Regulation by Dachsous and Fat Protocadherins

“…Although Fat4 ICD contains conserved blocks of amino acids, it fails to regulate Hippo and PCP in flies ( Pan et al, 2013 ). Mutations in Fat4 and DCHS1 are associated with Van Maldergem and Hennekam syndrome and many cancers ( Mansour et al, 2012 ; Cappello et al, 2013 ; Alders et al, 2014 ; van der Ven et al, 2017 ). Mouse knock outs of Fat4 and Dchs1 exhibit developmental defects in kidney, brain, lymphatic and skeletal systems ( Saburi et al, 2008 ; Mao et al, 2011a ; Saburi et al, 2012 ; Zakaria et al, 2014 ; Durst et al, 2015 ; Kuta et al, 2016 ; Crespo-Enriquez et al, 2019 ).…”

FAT4 Fine-Tunes Kidney Development by Regulating RET Signaling

“…Mutations in the atypical cadherin FAT4 cause Van Maldergem syndrome, of which CAKUT is a commonly observed feature (Alders et al, 2014;Cappello et al, 2013). FAT4 variants were also identified in whole-exome sequencing studies of CAKUT patients (van der Ven et al, 2017). In mice, Fat4 deletion leads to kidney defects reminiscent of CAKUT, including multicystic disease (Saburi et al, 2008;Saburi et al, 2012) and reduced nephron number (Bagherie-Lachidan et al, 2015;Mao et al, 2015;Das et al, 2013).…”