Original Article

Emerging Epidemiological Data on Rare Intellectual Disability Syndromes from Analyzing the Data of a Large Iranian Cohort

Cite this article as: Zare Ashrafi F, Akhtarkhavari T, Fattahi Z, Asadnezhad M, Beheshtian M, Arzhangi S, et al. Emerging epidemiological data on rare intellectual disability syndromes from analyzing the data of a large iranian cohort. Arch Iran Med. 2023;26(4):186-197. doi: 10.34172/aim.2023.29

Introduction

Intellectual disability (ID) is a frequent neurodevelopmental disorder diagnosed with cognitive and adaptive deficits before the age of 18 years.¹ ID is estimated to affect 1%–3% of the global population. It can manifest as an isolated clinical manifestation or as a syndromic phenotype, as well as other physical and mental abnormalities such as behavioral problems. Based on etiology, ID can happen due to both genetic factors and pre-and post-natal environmental factors.² Genetic factors contribute to a significant number of ID cases, and studies show that the most severe and profound ID patients are affected by monogenic disorders.^2,3 Based on SysNDD (a database that contains a catalogue of published genes implicated in neurodevelopmental disorders; last update: 6/25/2022), out of 1679 genes involved in ID, 982 show an autosomal recessive (AR) mode of inheritance, 527 exhibit autosomal dominant (AD) inheritance, 154 genes show X-linked inheritance, and others are involved in ID through mitochondrial inheritance and somatic mutations.⁴ Prior to the advent of next-generation sequencing (NGS), the diagnosis of monogenic ID was not sufficiently fast and efficient. However, with the introduction of this technology, the identification of disease-causing variants in monogenic cases of ID has improved drastically.⁵ Moreover, epidemiological studies of ID in inbred countries can provide reliable data about the most prevalent ID genes or gene groups. As shown in SysNDD, autosomal recessive intellectual disability (ARID) is one of the important forms of monogenic IDs. This form of ID is a clinically and genetically extremely heterogeneous condition and has major contribution to the etiology of ID.⁶ It is estimated that in outbred countries, ARID accounts for about 10% of all diagnosed ID cases and contributes to 15–20% of all undiagnosed patients.^6,7 At the same time, in countries with a high rate of parental consanguinity, the incidence of ARID shows a three-to four-fold increase, and rare ARIDs are more common among these populations.^1,6 Although a large number of ARID genes have been identified, the abundance of these genes remains unrecognized, and there is no extensive targeted NGS platform for diagnosing ARIDs with a high confidence rate.⁶ Countries with a high rate of parental consanguinity provide an excellent opportunity for identification of the remaining novel genes involved in ARIDs. Since Iran is a Middle Eastern country with a parental consanguinity rate of approximately 40%, it provides a suitable population reservoir for the epidemiological study of IDs, especially ARIDs.¹ The main goal of this study was to investigate the prevalence of genes identified using NGS in a large ID cohort at the Genetics Research Center of the University of Social Welfare and Rehabilitation Sciences. To the best of our knowledge, there is no comprehensive targeted NGS platform to detect ID genes in our country; therefore, considering the large sample size of this cohort, the present study may be the first step towards the design of an NGS platform for the diagnosis of ID in our country. We also compared the results of our study with those of several similar studies from other groups in consanguineous families originating from the Middle East to investigate overlapping gene defects with neighboring countries.

Materials and Methods

The epidemiological data obtained for this study were extracted from unpublished data and articles previously published by our research team.^1,8-10 In order to develop the cohort, we established a genetic counseling network from all 31 provinces of Iran to include all ethnic groups in our country. Iranian families were referred by physicians or clinical geneticists from all over the country.¹¹ The above-mentioned cohort consisted of a total of 1295 Iranian families who were referred to the Genetics Research Center of the University of Social Welfare and Rehabilitation Sciences (Iran) between 2004 and 2021 to identify genetic causes of ID. We performed total population sampling on our Iranian ID cohort. We defined the exclusion criteria as follows: families with chromosomal abnormalities, families with Fragile X syndrome, and inconsistent families. In 2011, our team studied 136 consanguineous families and applied homozygosity mapping, exon enrichment and targeted next generation sequencing.⁹ In another study, we performed whole-genome sequencing and/or whole exome-sequencing on 404 consanguineous families;¹ it should be mentioned that these families also included undiagnosed families from our previous study. In 2019, we applied whole exome-sequencing to 100 sporadic ID cases.⁸ We also added ID families from the unpublished data. In total, we had 619 Iranian families with ID with definitive diagnoses of the genetic causes of this disorder. To identify the most prevalent genes in our cohort, data extraction was performed using the R program version 4.1.2.

We also compared the most prevalent genes with multiple papers that published their ID cohorts. Since Iran has a high consanguinity rate, we chose papers from countries with high rates of consanguinity. These include papers from Pakistan and the Arabs of West Asia and North Africa.^12-18 Table S1 lists the genes used for the comparison. In the comparison of genes among the three groups, the following items were excluded.

1. Families with copy number variations

2. Families with multiple candidate genes

3. Samples that were investigated by a method other than NGS

We should mention that in this study, we did not have any information about ethnicity groups in other ID cohort papers, so we could not compare our data of ethnicity groups with the same ethnicity in neighboring countries.

Results

Out of 619 of the 1295 families in our ID cohort, we found 56 families that were reported twice in our cohort (56 families with mutations in 36 genes) and 65 families with a gene that was reported at least three times within the cohort (65 families with mutations in 17 genes). Based on the function of the genes, we categorized our most common genes, as depicted in Figure 1, and the number of families with mutations in each category is shown in Figure 2.

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Figure 1.

The Most Commonly Reported Genes or Gene Groups in our Cohort.

Figure 1.

The Most Commonly Reported Genes or Gene Groups in our Cohort.

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Figure 2.

Number of Families with the Most Common Mutated Genes or Gene Groups in Our Cohort.

Figure 2.

Number of Families with the Most Common Mutated Genes or Gene Groups in Our Cohort.

Further detailed data regarding the putative function of each gene in the pathogenesis of ID and related phenotypes of each gene/gene group are presented in Table 1 and Table 2. Furthermore, for multiple genes, we found two unrelated affected families, as listed in Table 3.

Comparison of our Study with Seven Studies Reporting ID Cohorts

We compiled two lists of reported ID genes among seven studies from neighboring countries with a high consanguinity rate that included ID cohorts.^12-18 This comparison resulted in the Venn diagram depicted in Figure 3. We also extracted repetitive genes (Supplementary File 1, Table S1) embedded in these three lists and compared them by depicting another Venn diagram shown in Figure 4.⁷⁶ The details of these comparisons are shown in Table 4. For both of these comparisons, copy number variations were excluded.

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Figure 3.

Venn Diagram Showing ID Genes Reported in our Cohort and the Pakistani and Arab Groups.

Figure 3.

Venn Diagram Showing ID Genes Reported in our Cohort and the Pakistani and Arab Groups.

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Figure 4.

Venn Diagram Showing Repetitive ID Genes Reported in our Cohort and the Pakistani and Arab Groups.

Figure 4.

Venn Diagram Showing Repetitive ID Genes Reported in our Cohort and the Pakistani and Arab Groups.

Discussion

Based on an epidemiological study of a large Iranian ID cohort, we were able to categorize the most common ID genes into 17 groups (AP4 complex, ASPM, WDR62, C2H2-Zinc fingers, exosome complex genes, General transcription factor IID subunits, VPS13B, SRD5A3, LARP7, calpain genes, tRNA methyltransferases, kinesins, DEAD-box helicases, L2HGDH, LINS1, TMEM67, and BBSome complex genes). Each group was repeatedly reported for at least three families in our cohort. Because of the high consanguinity rate in our population, 87.87% of these genes demonstrated an AR mode of inheritance. The most common syndromic ID in our study was AP4 deficiency syndrome, which was reported in 12 families and the most common non-syndromic ARID gene was ASPM.

For 36 ID genes, we could identify two unrelated families. For several genes, we found two unrelated families with the same mutations. These included families with (NC_000008.10:g.100732719del, p.Phe2293Leufs*24) in VPS13B, families with (NC_000012.11:g.117274037T > C, p.Cys384Arg) in RNFT2,and families with (NC_000019.9:g.1398999del, p.Gly164Alafs*14) in GAMT. In another study in 2015, Rafiq et al reported (p.Phe2293Leufs*24) in two unrelated Pakistani families of Baloch population.⁷⁷ On the other hand, for the recurrent variant in TMEM67, Dehghani et al found the same mutation among 12 Iranian nuclear families and suggested the variant as a founder mutation in the Iranian population.⁷⁸ Our study supports this hypothesis and confirms the prioritization of this variant for the diagnosis of Iranian patients with Joubert syndrome. At the same time, more studies are needed to confirm our hypothesis. Studies have shown that the variant of GAMT has been reported frequently in various families from Turkey, Israeli Arabs, Italy, and Iran.^1,79-81 It seems that the glycine at position 164 is a highly conserved amino acid, and a mutation at this position is one of the most prevalent alterations in GAMT.

According to HGMD and ClinVar, worldwide epidemiological studies on ARID showed that only a small number of these genes appear to have frequent variant reports, including GALT, VPS13B, ASPM, SPG11, MUT, GLDC, CEP290, POLG, LAMA2, and SMPD1.⁶ Two of these genes (VPS13B, ASPM) were also frequent in our cohort. In 2018, Jamra⁶ estimated that because both these syndromic genes have been well-known for a long time, a large number of reports are available. Although these genes have been known for a long time, our cross-sectional data showed a high prevalence of both genes, suggesting that they are two prevalent ARID genes.

The comparison of ID genes between our Iranian cohort, the Pakistani cohort, and Arab cohorts showed that Iran and Arabs have more common genes in comparison to Pakistani cohort. At this stage, we cannot claim that this similarity in ID genes is due to a more similar genetic background between these two groups of people, and more comprehensive studies are needed. We found 14 genes common between the three groups including ADGRG1, AP4M1, AP4S1, ATP8A2, ATRX, FMN2, MAN1B1, MAN2B1, MBOAT7, METTL5, TRAPPC9, TRMT1, VPS13B, and WDR62. The first three genes (AP4M1 and AP4S1 cause AP4 deficiency syndrome and ADGRG1 causes bilateral frontoparietal polymicrogyria) are repeated among these three groups of people, and they seem to be among the most common ID genes in consanguineous marriages.

Along with much better recognition of the role of genetic factors in ID in recent decades, the gap in epidemiological studies of genetic factors in ID has become more evident, and a large number of genes involved in this phenotype are yet to be discovered. Defining the prevalence of ID-mutated genes in Iran and having accurate statistical data help us make better strategic decisions on genetic and clinical diagnostics of IDs in the Iranian population and prevent the occurrence of such costly disabilities. Due to the large sample size, our data could enhance the design of targeted NGS platforms, mainly population-specific diagnostic tools.

Supplementary Files

References

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