Galloway-Mowat Syndrome 6

A number sign (#) is used with this entry because of evidence that Galloway-Mowat syndrome-6 (GAMOS6) is caused by homozygous or compound heterozygous mutation in the WDR4 gene (605924) on chromosome 21q22.

Description

Galloway-Mowat syndrome is a phenotypically heterogeneous disorder characterized by neurodevelopmental defects combined with renal-glomerular disease manifest as nephrotic syndrome and proteinuria. Most patients with GAMOS6 also have growth deficiency with variable microcephaly, and the renal disease may be age-dependent. Additional variable endocrine abnormalities have also been reported (summary by Braun et al., 2018).

For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).

Clinical Features

Trimouille et al. (2018) reported 2 teenaged sisters, born of unrelated French parents, with mild microcephaly (-1.27 to -2.18 SD), mild overall growth retardation, and severe developmental delay. They walked by age 3.5 years, spoke first sentences at age 6 years, and had behavioral abnormalities, including stereotypic movements, sudden bursts of laughter, and sleep disturbances. Mild dysmorphic facial features included periorbital fullness, epicanthal folds, anteverted nostrils, wide mouth with downturned corners, high-arched palate, and small teeth. The younger sister had growth hormone deficiency, and both were treated with growth hormone with good clinical response. They had pubertal onset at age 14 years, but no progression, suggesting partial hypogonadotropic hypogonadism; both were also treated with estradiol. Radiographs showed delayed bone age, and brain imaging showed vermian atrophy of the cerebellum. Neither patient had seizures. Extensive metabolic analysis did not show any abnormalities.

Chen et al. (2018) reported a 6-year-old boy with global developmental delay and poor overall growth. He started to walk at age 2 years, was unable to form a complete sentence at age 6, and showed impaired intellectual development (Developmental Quotient (DQ) less than 50). He did not have dysmorphic features or seizures, and brain imaging and EEG were normal. Head circumference was not given, but it was noted to be smaller than normal, and his height was -2 SD.

Braun et al. (2018) reported 4 sibs, born of Indian parents who denied consanguinity, with a complex disorder comprising poor growth, impaired development, and age-dependent nephrotic syndrome. The patients ranged in age from 4 to 15 years. They had poor overall growth, including microcephaly, short stature, and low weight, mildly to moderately impaired intellectual development, and impaired performance at a regular school. Two patients had fifth finger clinodactyly. Brain imaging performed on 1 patient was normal, and none of the patients had seizures. The 3 older patients had nephrotic syndrome with proteinuria, and renal biopsy of 2 patients showed focal segmental glomerulosclerosis with podocyte foot process effacement. However, overall renal function was preserved, and only 1 patient required treatment with immunosuppressive drugs. The 3 older sibs also had mild hypothyroidism. The 4-year-old sib had no signs of renal impairment or thyroid dysfunction, suggesting that these features may be age-dependent.

Inheritance

The transmission pattern of GAMOS6 in the family reported by Braun et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sisters, born of unrelated French parents, with GAMOS6, Trimouille et al. (2018) identified compound heterozygous mutations in the WDR4 gene (R170Q, 605924.0002 and c.911_927dup, 605924.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.

In a 6-year-old Chinese boy with GAMOS6, Chen et al. (2018) identified compound heterozygous mutations in the WDR4 gene (D164A, 605924.0004 and c.940dupC, 605924.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Molecular modeling suggested that the D164A variant may reduce protein stability and/or interfere with stabilization of the WDR4/METTL1 (604466) complex. Functional studies of the variants and studies of patient cells were not performed.

In 4 sibs, born of unrelated Indian parents, with GAMOS6, Braun et al. (2018) identified a homozygous splice site mutation in the WDR4 gene (605924.0006). The mutation, which was found by whole-exome sequencing, was present only once in heterozygous state in the ExAC database (frequency of 0.017%). Functional studies of the variant and studies of patient cells were not performed. Braun et al. (2018) noted that the Indian patients had age-dependent renal involvement, suggesting that the phenotype may be dependent on the specific mutation or allele. The authors also suggested that patients with WDR4 mutations be screened for renal disease.