Genotypic and phenotypic spectrum of Galloway-Mowat syndrome in Kuwait

Abstract

Introduction

Galloway-Mowat syndrome (GAMOS) is a rare genetic disorder that is characterized by microcephaly and neurological and renal abnormalities. Ten types of GAMOS exist based on the underlying implicated gene. The purpose of this study was to investigate the phenotypic and genotypic spectrum of GAMOS in Kuwait.

Methods

We queried the Kuwait Medical Genetic Center database for subjects with neuro-renal or neurological phenotypes and pathogenic variants in any of the ten known genes associated with GAMOS.

Results

We identified eight subjects from five unrelated families with biallelic pathogenic WDR73 variants and a diagnosis of GAMOS type 1 (GAMOS1). All subjects had global developmental delay, microcephaly, tone abnormalities and impaired activities of daily living. Renal features were observed in more than half of the subjects (5/8 subjects) and included proteinuria, nephrotic syndrome, and end-stage renal disease (ESRD). More than half of the subjects (5/8 subjects) died by 5–10 due to ESRD, including one of which who died due to unknown cause while the rest (ages 3–5 years) are still living with no renal features.

Two possible founder variants were identified, including c.287 G>A;p.Arg96Lys in three unrelated families of Kuwaiti, Iraqi, and/or Syrian ancestry, and c.767 G>A;p.Arg256Gln in two unrelated families of Kuwaiti or Syrian ancestry.

Conclusion

GAMOS1 is the most prevalent form of GAMOS in Kuwait, likely due to the presence of two WDR73 regional founder variants. These findings contribute to the global understanding of GAMOS and highlight the important contribution of regional genetic studies in diverse populations to rare disease research.

Graphical Abstract

In this paper, we describe the clinical and genotype features of 8 cases from 5 unrelated families of Kuwaiti, Iraqi, and Syrian ancestry with Galloway-Mowat type 1. The cases were found to have two recurrent variants (c.287 G>A;p.Arg96Lys & c.767 G>A;p.Arg256Gln) suggestive of two possible regional founder WDR73 variants.

Introduction

Galloway Mowat syndrome (GAMOS) is a rare autosomal recessive disease that is characterized by central nervous system abnormalities such as microcephaly, developmental delay, seizures and intellectual disability along with renal abnormalities such as nephrotic syndrome and end stage renal disease (ESRD) [1]. Other clinical features in GAMOS include hiatal hernia, optic atrophy, and intrauterine growth restriction (IUGR) [2], [3]. Symptoms usually start appearing from birth to early childhood and the prognosis usually varies depending on the age of onset. As such, early-onset nephrotic syndrome may lead to end stage renal disease (ESRD) resulting in early death, whereas later onset of nephrotic syndrome may result in longer survival rate [4], [5]. In families with previous affected children with GAMOS, the diagnosis can be even suspected prenatally in future pregnancies on prenatal ultrasound by the detection of microcephaly, IUGR and oligohydramnios, which is further supported by the detection of abnormal sulcation, cortical gyral malformations, and cerebellar atrophy by prenatal brain magnetic resonance imaging (MRI) [3], [6]. While there is no cure for GAMOS, early recognition and symptomatic treatments, including use of hemodialysis or renal transplant, can aid in increasing the quality of life in these patients [7].

Ten types of GAMOS currently exist depending on the underlying molecular etiology [8]. Type 1 is caused by pathogenic variants in the WD repeat-containing protein 73 (WDR73) gene, whereas types 2–10 are caused by pathogenic variants in LAGE3, OSGEP, TP53RK, TPRKB, WDR4, NUP107, NUP133, GON7, and YRDC, respectively [8]. Almost all types of GAMOS have an autosomal recessive inheritance pattern due to biallelic pathogenic variants in the genes listed above except for LAGE3-associated GAMOS type 2 which has an X-linked recessive inheritance thus primarily affect males [8].

GAMOS is an extremely rare syndrome. Collectively, only 150 cases have been reported worldwide [8], with over 50 cases being due to biallelic pathogenic variants in WDR73 [2], [5], [7], [9], [10], [11], [12], [13], [14], [15]. In this study, we investigate the genotype and phenotype spectrum of GAMOS in Kuwait, with particular focus on GAMOS type 1 (GAMOS1) caused by biallelic variants in WDR73, in effort to add to the global effort of understanding this rare disease.

Methods

Standard protocol approvals, registration, and patient consents

The research study was approved by the Research and Ethical Committee of the Ministry of Health in Kuwait (ethical protocol# 2022/2181). It was conducted according to the ethical principles of Declaration of Helsinki. Aggregate anonymized clinical data was included in the manuscript. Informed consent was waived by the ethical board given the retrospective nature of the study.

Genotype analysis

We reviewed the database of Kuwait Medical Genetics Center (KMGC), the only tertiary referral genetic center in Kuwait, for cases diagnosed clinically and molecularly with GAMOS based on the presence of a neurological or neuro-renal phenotype along with the identification of biallelic variants in any of the following genes known to be associated with GAMOS: WDR73, LAGE3, OSGEP, TP53RK, TPRKB, WDR4, NUP107, NUP133, GON7, and YRDC.

The probands from all five families were diagnosed through proband exome sequencing (ES). The probands from Families 1–5 had exome sequencing done locally at the KMGC, at private or research laboratories. Segregation studies were performed on samples from available members of the families. The diagnosis was strongly suspected clinically in the affected siblings of the probands in Families 1 and 5 but genetic confirmation was not possible since they died by the time of molecular diagnosis was established in the probands. These subjects were still included in the study based on the clinical diagnosis of GAMOS (Table 1).

Table 1.

Demographic and variant information of subjects with biallelic WDR73 variants in this study.

Family no.	Family 1			Family 2	Family 3	Family 4	Family 5
Subject no.	1 (IV-3)	2 (IV-8)	3 (IV-10)	4 (IV-4)	5 (IV-1)	6 (V-2)	7 (IV-4)	8 (IV-7)
Demographic information
Ethnicity/Ancestry	Kuwaiti/Syrian			Kuwaiti/Iraqi	Syrian	Undeclared/Kuwaiti	Syrian
Sex	F	F	F	M	M	F	M	M
Age (years)	Died at 10 years (ESRD)	Died at 10 years (ESRD)	Died at 9 years (ESRD)	3 years	4 years	5 years	Died at 5 ½ years (ESRD)	Died at 21/2 years
Variant Information
Type of test	NT	NT	ES	ES	ES	ES	ES	NT
c.DNA (NM_032856.9)	NT	NT	c.287G>A	c.287G>A	c.287G>A	c.767G>A	c.767G>A	NT
Amino acid	NT	NT	p.Arg96Lys	p.Arg96Lys	p.Arg96Lys	p.Arg256Gln	p.Arg256Gln	NT
Variant status	NT	NT	Hmz	Hmz	Hmz	Hmz	Hmz	NT

Abbreviation: ES, exome sequencing, F, female; Hmz, homozygous; M, male, NT, not tested

Phenotype analysis

A retrospective chart review was performed to delineate the clinical features of the disease in all subjects. We reviewed all available neurology, nephrology, and genetic reports available. Brain images were available for review by a certified neuro-radiologist (N.Y.A) on two subjects (Subject 3 from Family 1 and Subject 8 from Family 5). Serial renal ultrasounds were available for review in one subject (Subject 7 from Family 5). The frequency of each clinical and radiological feature was calculated only in subjects with available data. If the data was not available, the case was excluded from the frequency calculation.

Results

Clinical phenotype

We identified eight affected individuals from five unrelated families, all of whom were diagnosed with GAMOS1 due to biallelic homozygous variants in WDR73. No affected subjects with pathogenic variants in the other genes associated with GAMOS were identified in the database. Table 1 summarizes the demographic and variant information in all our subjects from this study. Table 2 summarizes the clinical features, renal findings, and brain imaging findings of affected individuals with GAMOS1 in previously published studies and aggregate clinical features of subjects in this study. Individual case reports can be found in the Supplemental material.

Table 2.

Summary of the clinical features of all cases with biallelic WDR73 variant reported to date.

Study name	Previous reports											This report	Total to date
	[7]	[14]	[9]	[2]	[11]	[15]	[12]	[5]	[10]	[13]	Previous total (%)	Total (%)
Neurological features
GDD/ID	3/3	2/2	30/30	10/10	7/7	2/2	1/1	4/4	1/1	4/4	64/64 (100%)	8/8 (100%)	72/72 (100%)
Microcephaly	3/3 (P)	0/2	24/30	9/10	7/7	0/2	1/1	4/4 (P)	1/1	4/4	53/64 (83%)	8/8 (100%)	61/72 (85%)
Spasticity/peripheral hypertonia	2/3	2/2	NR	6/10	4/7	NR	0/1	4/4	1/1	3/4	22/32 (69%)	5/5 (100%)	27/37 (73%)
Axial hypotonia	3/3	2/2	26/30	6/10	7/7	0/2	1/1	4/4	1/1	3/4	53/64 (83%)	6/7 (86%)	59/71 (83%)
Dystonia	0/3	0/2	26/30	8/10	NR	2/2	NR	NR	NR	3/4	39/51 (76%)	3/4 (75%)	42/55 (76%)
Seizures	2/3	2/2	12/30	3/10	3/7	0/2	NR	1/4	0/1	2/4	25/63 (40%)	5/8 (63%)	30/71 (42%)
Ataxia	NR	NR	26/30	5/9	2/7	2/2	NR	NR	NR	1/4	36/52 (69%)	NR	36/52 (69%)
Activities of daily living
Speech disability	NR	2/2	29/30	9/10	7/7	2/2	1/1	NR	1/1	3/4	54/57 (95%)	6/6 (100%)	60/63 (95%)
Limited mobility	NR	2/2	27/30	10/10	7/7	2/2	1/1	NR	1/1	3/4	53/57 (93%)	6/6 (100%)	59/63 (94%)
Feeding problems	NR	NR	NR	6/10	NR	NR	1/1	NR	1/1	1/1	9/13 (69%)	7/8 (88%)	16/21 (76%)
Irregular sleep pattern	NR	NR	NR*	4/9	NR	NR	NR	NR	NR	NR	4/9 (44%)	4/6 (67%)	8/15 (53%)
Renal features
Proteinuria	2/3	1/2	11/30	4/7	4/7	1/2	0/1	4/4	0/1	3/4	30/61 (49%)	5/8 (63%)	35/69 (51%)
Nephrotic syndrome	2/3	1/2	17/30	1/5	2/7	0/2	0/1	4/4	0/1	1/4	29/63 (46%)	5/8 (63%)	34/71 (48%)
End-stage renal disease	1/3	0/2	15/30	2/10	1/7	0/2	0/1	4/4	0/1	0/4	23/64 (36%)	4/7 (57%)	27/71 (38%)
FSGS on Renal biopsy	2/3	ND	3/3	3/3	1/2	ND	ND	3/3	ND	ND	12/14 (86%)	ND	12/14 (86%)
Ophthalmological features
Optic atrophy	3/3	2/2	28/30	8/9	1/7	2/2	1/1	4/4	1/1	2/4	52/63 (83%)	4/6 (67%)	56/69 (81%)
Strabismus	NR	1/2	NR	7/10	NR	NR	1/1	1/4	1/1	NR	11/18 (61%)	1/3 (33%)	12/21 (57%)
Retinopathy	NR	NR	NR	2/6	NR	NR	1/1	NR	1/1	NR	4/8 (50%)	1/3 (33%)	5/11 (45%)
Ptosis	NR	0/2	NR	2/10	NR	NR	1/1	NR	NR	NR	3/13 (23%)	0/3 (0%)	3/16 (19%)
Brain MRI findings
Cerebellar atrophy/DWM	3/3	2/2	2/2	7/7	7/7	1/1	0/1	4/4	1/1	4/4	31/32 (97%)	4/6 (67%)	35/38 (92%)
Brain atrophy	2/3	2/2	2/2	4/7	NR	NR	0/1	3/4	NR	1/4	14/23 (61%)	1/6 (17%)	15/29 (52%)
Thin Corpus Callosum	2/3	2/2	2/2	NR	3/7	NR	0/1	0/4	NR	1/4	10/23 (43%)	1/6 (17%)	11/29 (38%)
Myelination defects	0/3	2/2	NR	1/7	NR	NR	1/1	NR	NR	NR	4/13 (31%)	1/6 (17%)	5/19 (26%)
Basal ganglia degeneration	0/3	0/2	0/2	2/7	NR	NR	0/1	NR	NR	2/4	4/19 (21%)	0/6 (0%)	4/25 (16%)
Miscellaneous
Short stature	NR	NR	NR	8/9	1/2	1/2	NR	NR	NR	2/4	12/17 (71%)	5/7 (71%)	17/24 (71%)
Facial dysmorphism	3/3	2/2	NR	NR	5/7	0/2	1/1	2/2	NR	1/4	13/17 (76%)	4/8 (50%)	17/25 (68%)

Abbreviations: DWM, Dandy-Walker malformation; FSGS, focal segmental glomerulosclerosis; GDD, global developmental delay; ID, intellectual disability; P, progressive/postnatal.* reported in majority yet number unspecified.

Of our eight subjects, there were four females and four males; four of them died at the ages five, nine, ten, and ten years due to ESRD while the cause of death was not documented in the fifth subject (Table 1). Three subjects are still alive at the ages three, four, and five years. Global developmental delay (GDD)/intellectual disability (ID) and microcephaly were evident in all our individuals (8/8; 100%). Tone problems were common, with all five evaluated individuals (100%) exhibiting peripheral hypertonia or spasticity while axial hypotonia was observed in six out of seven individuals (85.7%). Furthermore, other common neurological features in our cohort included dystonia in three out of four (75%) subjects, and seizures in five out of eight (62.5%) subjects.

The disease affected various aspects of daily living, including mobility and speech, in all evaluated individuals (6/6; 100%). It also affected feeding in seven out of eight (87.5%) subjects and affected sleep pattern in four out of six (66.6%) subjects.

At the time of the study, five out of eight subjects exhibited renal features. Their ages ranged from two and half to ten years old at their last assessment. The remaining three subjects with no renal manifestations were between three and five years old at their last examination. Renal findings included proteinuria and nephrotic syndrome, present in five out of eight individuals (62.5%), and ESRD which occurred in four out of seven individuals (57.1%) and was the cause of death in four of the five deceased subjects. None of our subjects underwent renal biopsy.

Ophthalmological abnormalities were also observed among our subjects. Optic atrophy was present in four out of six individuals (66.6%), while strabismus and retinopathy were each identified in only one out of three individuals (33.3%). Nystagmus was also reported, although none of the subjects had ptosis.

Brain imaging findings in our subjects included Dandy-Walker malformation/cerebellar atrophy by report in four out of six individuals (67%), and cerebral atrophy in only one out of six (17%). One subject had thinning of corpus callosum and white matter defect (Fig. 2c-d). None of the subjects had basal ganglia degeneration. Serial abdominal ultrasound on one subject showed evidence of progressive nephropathy (Fig. 2e-h).

Fig. 2.

selected images of subjects with WDR73-related Galloway-Mowat syndrome type 1 included in this study. a) Axial T2-weighted image of the brain of Subject 3 (IV-10) from Family 1 at the age of 1 year at the level of basal ganglia showing normal basal ganglia, thalamus as well as normal brain parenchyma and myelination for age. b) Mid-sagittal T1-weighted image of the brain of Subject 3 (IV-10) from Family 1 showing normal corpus callosum, cerebellum and brainstem. c) Axial T2-weighted image of the brain of Subject 8 (IV-7) from Family 5 at 5 days of life at the level of the basal ganglia showing increased T2 hyperintensity involving the deep white matter of the bilateral frontal lobes (thin arrow). Cavum septum pellucidum is seen (thick arrow) with normal myelination of the PLIC (posterior limb of the internal capsule) (arrowhead). d) Mid-sagittal T-weighted image of the brain of Subject 8 (IV-7) from Family 5 at 5 days of life showing small head size (microcephaly) with thin corpus callosum (thin arrow) and small pons (thick arrow). Prominent infra cerebellar CSF space of mega cisterna magna is also seen (star). e) & f) showing normal ultrasound of the bilateral kidneys of Subject 7 (IV-4) from Family 5 at the age of two-years-old. g) & h) showing follow up ultrasound study of Subject 7 (IV-4) from Family 5 at the age of 5 years old showing interval increased parenchymal echogenicity denoting nephropathy.

Additional findings included short stature in five out of seven individuals (71%) and facial dysmorphism documented in four out of eight individuals (50%).

Genetic/molecular findings

Table 1 summarizes the demographic and variant information of all subjects reported herein with biallelic WDR73 variants. The five probands from the five different families had two different main pathogenic variants in WDR73. These families reported ancestry spanning three different neighboring countries, suggesting that these two variants may represent founder variants within the region. Families 1–3 with the c.287G>A;p.Arg96Lys variant had Kuwaiti, Iraqi and/or Syrian ancestry while Families 4–5 with the c.767G>A;p.Arg256Gln had Kuwaiti or Syrian ancestry.

Segregation study was performed on available samples in Families 1, 2, and 3 as indicated on Fig. 1 and the result conformed with Mendelian expectations.

Fig. 1.

pedigrees of all families with WDR73-related Galloway-Mowat syndrome type 1 included in the study. Circle indicates a female subject while square indicates a male subject. Note that affected subjects with GAMOS1 are shaded in black. Genotype indicated under each tested subject.

The first missense variant c.287G>A;p.Arg96Lys substitutes arginine with lysine at amino acid position 96 and localizes to the N-terminal region of the protein structure. It is absent in GnomAD v.2.1.1 control database in both homozygous and heterozygous states (minor allele frequency [MAF] of 0). It is predicted to be damaging by multiple prediction models, affect splicing (SpliceAI donor loss score of 0.89), and has a CADD score (GRCh37-v1.7) of 33. The residue is conserved across species (phyloP100 score of 5.391).

The second missense variant c.767G>A;p.Arg256Gln substitutes arginine with glutamine at amino acid position 256 and localizes to the WD40 region. It is absent in GnomAD v.2.1.1 control database in both homozygous and heterozygous states but is found on GnomAD v.4.1.0 in heterozygous state in ten subjects including a Middle Eastern male (MAF: 0.00016). It is predicted to be damaging by some prediction models. It affects splicing (SpliceAI acceptor gain score of 0.93), and has a CADD score (GRCh37-v1.7) of 35. The residue is conserved across species (phyloP100 score of 4.313).

Discussion

In this study, we report eight new subjects from five new unrelated families from Kuwait with GAMOS1 due to biallelic homozygous variants in WDR73. The subjects have brain, renal and ophthalmological features.

Neurological features including GDD/ID and microcephaly were prominent in all of our subjects, consistent with previously reported cases whereas these findings were observed in nearly all reported subjects (100% and 83%, respectively) [2], [5], [7], [9], [10], [11], [12], [13], [14], [15]. Microcephaly in GAMOS1 is typically progressive postnatal/secondary supporting the progressive nature of the disease [5], [7]. Axial hypotonia was around the same prevalence between ours and previously reported cases, 86% and 83% respectively [2], [5], [7], [9], [10], [11], [12], [13], [14]. Dystonia was observed at same rate in our study compared to previous cases (76% vs 75%, respectively) [2], [9], [13], [15]. However, peripheral hypertonia/spasticity was a variable feature seen in all our subjects compared to more than half of previously reported cases (69%). Seizures were more common in our subjects compared to previously published cases (63% vs 40%) [2], [5], [7], [9], [11], [12], [13], [14]. Ataxia was not documented in any individuals from our cohort, although it has been reported as a common feature in 69% of cases described to date [2], [9], [11], [13], [15]. The higher prevalence of hypertonia/spasticity and seizures, along with the absence of ataxia in our cohort compared to previously reported cases, may be attributed to differences in the age of subjects, the specific nature of the variant, or may reflect the broader neurological spectrum of the disease.

Limited mobility and speech disability were found in all of our individuals and almost all previously reported cases 93% and 95%, respectively, demonstrating significant impairment of activities of daily living in individuals with GAMOS1 [2], [9], [10], [11], [12], [13], [14], [15]. Feeding problems and irregular sleep patterns were slightly more prevalent in our cohort compared to previously reported cases (88% vs 69% for feeding issues and 67% vs 44% for sleep disturbances). This may suggest a slightly more severe or broader range of neurological involvement in our subjects.

Similar to the neurological findings, renal manifestations, such as proteinuria, nephrotic syndrome, and ESRD, were slightly more frequent in our cohort compared to previously published cases. Proteinuria and nephrotic syndrome were observed in 63% of our cases compared to 49–46% in earlier reports [2], [5], [7], [9], [11], [13], [14], [15]. Nephrotic syndrome in GAMOS1 is typically steroid resistant [5], [9], [16]. Over half of our cases developed ESRD, compared to just over one-third of the previously reported cases [2], [5], [7], [9], [11]. Renal abnormalities are inconsistent features in GAMOS1, with a variable age of presentation [2]. Nevertheless, ESRD remains the leading reported cause of death in GAMOS1, occurring in nearly half of affected individuals with the average age of death at around 11 years [9]. This was consistent with our study in which half of our subjects were deceased by age 5–10 years due to ESRD, three of which had the p.Arg96Lys variant. Previously reported cases carrying the same pathogenic p.Arg96Lys variant demonstrated a variable age of onset for renal involvement [2], [11]. Renal finding in previously reported individuals with the p.Arg96Lys showed notable variability; they were absent at 3.5 years of age in a Saudi patient and present at 4 years in a Palestinian girl while proteinuria started at 16 years in an Indian patient. This variability argues against a clear genotype-phenotype correlation [2], [11], [12]. Renal biopsy performed in some previously reported cases revealed focal segmental glomerulosclerosis (FSGS) in 86% of individuals, with collapsing FSGS (cFSGS) described in four cases and podocyte hypertrophy noted in two cases [2], [5], [7], [9], [11]. Rare findings included diffuse mesangial sclerosis in one subject [11], and a normal biopsy in another [7]. None of the individuals in our cohort underwent renal biopsy.

In contrast to the neuro-renal manifestations, ophthalmologic features were slightly less frequent in our cohort compared to previous reports. Optic atrophy was observed in 67% of our subjects versus 83% in previous cases [2], [5], [7], [9], [10], [11], [12], [13], [14], [15]. Strabismus and retinopathy were observed in 33.3% of our cohort, compared to 61% and 50% of previous subjects, respectively [2], [5], [10], [12], [14]. Ptosis was not observed in our cohort, whereas it was reported in 23% of previously published cases [2], [12]. This difference may suggest that the specific variant in our cohort is less likely to cause ophthalmologic involvement, or it may simply reflect the phenotypic variability within the disease spectrum.

Regarding the brain imaging findings, cerebellar atrophy/Dandy-Walker malformation was less frequently observed in our cohort compared to previous reports, where it was present in almost all documented cases; (67% vs. 97%) [2], [5], [7], [9], [10], [11], [13], [14], [15]. Similarly, brain atrophy was also much less common in our cases compared to previously reported cases; (17% vs. 61%) [2], [5], [7], [9], [12], [13], [14]. White matter abnormalities including thin corpus callosum and myelination defects were also less common in our cohort compared to previous cases; 17% vs 43% and 17% vs 31%, respectively. Additional radiological features reported in previous studies, but not seen in our cohort, included basal ganglia degeneration (21%) [2], [9], [11], [12], [13]. GAMOS1 is known to be a progressive disease [9], and these radiological features may develop over time, potentially explaining their lower prevalence in our cohort. It is also possible that our subjects underwent brain imaging at a younger age due to more severe neurological features and earlier clinical presentation, which may have limited the detection of later-emerging features.

Other common reported clinical features in both our cohort and previously published cases included short stature, observed in more than two thirds of individuals [2], [11], [13], [15]. Facial dysmorphism was documented in 50% of our subjects compared to 76% in prior reports [5], [7], [11], [13], [14]. It is important to note that the assessment of facial dysmorphism can be subjective and may vary depending on the evaluating clinician.

WDR73 encodes a protein that contains 378 amino acids in form of multiple WD40 repeats, which are 40 amino acids-containing structural motifs that are usually terminating in a tryptophan-aspartic acid (W-D) dipeptide. These motifs act as a platform for protein-protein interactions facilitating signal transduction, protein degradation, and apoptosis by interacting with mitotic microtubules during cell division [17]. Along with these domains, there are distinct N-terminal and C-terminal regions. WDR73 is expressed in the renal glomeruli and infant and adult brains with highest expression in the Purkinje cells, cerebellum, and pyramidal neurons in the cerebral cortex [7]. Hence, pathogenic variants in WDR73 result in microtubules disorganization that change the shape and size of the nucleus, resulting in abnormal cerebral cortical growth, cerebellar hypoplasia, abnormal visual pathway development, and focal segmental glomerulosclerosis consistent with GAMOS [7], [11]. The pathogenic missense variant c.287 G>A;p.Arg96Lys in our subjects localizes to the N-terminal region while the missense pathogenic variant c.767 G>A;p.Arg256Gln we report herein localizes to the WD40 region.

These two variants identified in our cohort (c.767 G>A;p.Arg256Gln and c.287 G>A;p.Arg96Lys), likely represent founder mutations, contributing to the apparent overrepresentation of GAMOS1 in our study. The c.287 G>A;p.Arg96Lys variant, observed in three unrelated families from Kuwaiti, Iraqi, and Syrian ancestry in our study, has previously been reported in homozygous state in eight affected cases with GAMOS: one each from India [2], Saudi Arabia [12], and Syria [11], two subjects from Palestine [11], and two individuals of unspecified ethnicity; one from a large multicenter international study on steroid-resistant nephrotic syndrome [16], and another from pan-European study on undiagnosed rare disease [18]. These findings suggest that this variant may represent a founder mutation among individuals with ancestry from the Northern Arabian Peninsula and the Levant region, while its presence in isolated cases, such as the Indian subject, may indicate a recurrent mutation.

Similarly, the c.767G>A;p.Arg256Gln variant, observed in two unrelated families of Kuwaiti and Syrian origin in our cohort, was previously reported in a Tunisian child from the South [5]. This raises the possibility of a shared Arab founder or a recurrent variant within the region.

Unfortunately, due to the use of different laboratories and geographic separation of cases, haplotype analysis was not feasible. Future studies incorporating such analysis may help clarify the founder or recurrent nature of these variants.

Founder mutations are pathogenic disease-causing variants that become prevalent within a specific ethnic, ethno-religious, or geographic population or sub-population due to its inheritance from a common ancestor often leading to increased prevalence of a rare disease within the group if coupled with strict mating (endogamy and consanguinity) within the group [19]. A WDR73 founder mutation has been previously reported in the Amish community due to strict mating within the group leading to restricted gene pool. Similarly, numerous founder mutations have been described in the Arab population and contributed to many rare disease discoveries [19]. In Kuwait, there are many known founder mutations such as the Kuwaiti tribal EMC1 pathogenic variant causing cerebellar atrophy, visual impairment, and psychomotor retardation (CAVIPMR; OMIM #616875) and SLC19A3 Arab founder variant causing Biotin-thiamine-responsive basal ganglia disease (BTBGD; OMIM# 607483) [20], [21]. Recognizing these founder mutations can play a crucial role in improving the health care system [19]. It can help in cost-effective and rapid targeted screening guided by the disease phenotype based on pre-existing knowledge of the presence of founder mutations in the country or region. Subsequently, early clinical and molecular diagnosis can lead to timely intervention, which in some diseases might be lifesaving [19], [20]. Recognizing these mutations may also help us in public health and healthcare resource planning [19]. This can be achieved by implementing gene/variant panel testing for these founder mutations in premarital and newborn screening which can reduce disease burden through counseling and prevention, and lead to early case detection and treatment, thus decreasing morbidity and healthcare cost.

One main limitation of the study is that cases with clinical and/or molecular diagnosis of GAMOS that have been diagnosed in any of primary hospitals in Kuwait or the private sector or abroad and not sent to KMGC may have been missed from the KMGC database and this study.

In summary, we describe the phenotyping and genetic spectrum of GAMOS in Kuwait, highlighting GAMOS1 as the most prominent subtype, likely due to the presence of two potential founder WDR73 variants within the North Arabian Peninsula and Levant region. Our findings contribute to the global understanding of GAMOS and support efforts toward rapid diagnosis and targeted prevention strategies within the region.

Author contribution

Fares Alhammad and Dana Marafi contributed to drafting the manuscript and revising it critically for important intellectual content. Nawal Y Ali, Sumaya Alkanderi, Reem Elshafie, Laila Bastaki, Hind Alsharhan, Buthina Albash, and Dana Marafi contributed to data acquisition including clinical examination of patients, clinical images, sample collection, and genetic counseling. Fares Alhammad, Hind Alsharhan, and Dana Marafi contributed to the analysis and interpretation of the data and critical review of the manuscript. All authors approved the final manuscript and agreed to be accountable for all aspects of the work.

Funding

No external funding was received for this work.

Declaration of Competing Interest

Authors have no potential conflicts to report.

Appendix A. Supplementary material

Supplementary material

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.