Inborn Errors of Immunity in Jordan: First Report from a Tertiary Referral Center.

PURPOSE: Inborn errors of immunity (IEI) are a heterogeneous group of diseases with variable clinical phenotypes. This study was conducted to describe the epidemiology, clinical presentations, treatment, and outcome of IEI in Jordanian children. METHODS: A retrospective data analysis was conducted for children under 15 years diagnosed with IEI from the pediatric Allergy, Immunology, and Rheumatology Division-based registry at Queen Rania Children's Hospital, Amman, Jordan, between 2010 and 2022. RESULTS: A total of 467 patients, 263 (56.3%) males and 204 (43.7%) females, were diagnosed with IEI. The mean age at symptom onset was 18 months (1 week to 144 months), a positive family history of IEI was reported in 43.5%, and the consanguinity rate was 47.9%. The most common IEI category was immunodeficiencies affecting cellular and humoral immunity at 33.2%, followed by predominantly antibody deficiencies at 16.9%. The overall median diagnostic delay (range) was 6 (0-135) months; patients with a positive family history of IEI had a statistically significant shorter diagnostic delay. Pulmonary and gastrointestinal clinical features were the most common at 55.2% and 45.6%, respectively. The overall mortality was 33.2%; the highest rate was reported in severe combined immunodeficiency at 56.2%. CONCLUSIONS: The high minimal estimated IEI prevalence at 16.2/100,000 Jordanian children compared to the regional and worldwide data, with the diversities in clinical presentation and distribution of IEI categories in our cohort point to unique features of IEI in Jordanian children, call for national registry establishment, regional and international collaborative networks.

Consanguineous marriages, premarital screening, and genetic testing: a survey among Saudi university students.

Background: Marriage among cousins or close relatives, i.e., consanguinity, is prevalent in many parts of the world, especially the Muslim world. Across civilizations, cultural norms, religious beliefs, and economic factors affect consanguineous marriages (CMs); however, such marriages have social, genetic, and health repercussions. The present study investigated the university students' attitudes regarding CMs and factors influencing their attitudes at King Abdulaziz University (KAU), Jeddah, Kingdom of Saudi Arabia (KSA). Methods: This cross-sectional prospective study was conducted at KAU Jeddah in 2023. The questionnaire was distributed via electronic media (Emails, Facebook Messenger & WhatsApp). The convenience sampling technique was used to select participants, and descriptive and inferential statistics were used to analyze the data on SPSS-26. Results: A total of 1707 university students were part of the study (females, 1,198, 70.2%; males, 509, 29.8%). Almost half of the participants, 819 (48.0%), had parents with CMs. Most of the participants, 1,391 (81.5%), had CMs in the family. Half of the participants disagreed that parents consider marriage stable due to high compatibility and the same social relationship before and after marriage. About one-third of respondents said parents believe family marriage transmits cultural values and continuity and keeps wealth in the family. More than three-fourths of the participants stated that if marriage is arranged with first cousins, they will opt for genetic analysis (82.5%) and premarital counseling (85.2%). The personal attitudes of females (p < 0.001), undergraduate (p = 0.02), and health sciences students (p = 0.02) were more positive than their counterparts. Males (OR = 0.41; p < 0.001) and non-health sciences students (OR = 0.68; p = 0.01) were less likely to have significant positive attitudes than their counterparts. Among participants who had CM parents, males (OR = 0.397; p < 0.001) and non-health sciences students (OR = 0.60; p = 0.01) and urban residents (OR = 0.59; p = 0.01) had significantly lower odds of having a positive attitude than their counterparts. Conclusion: The practice of CMs is still prevalent in Saudi culture, with almost half of the participants having CM parents and the majority reporting these marriages in their families. Personal attitudes toward CMs were extremely positive. Most students prefer genetic testing and premarital counseling if marrying first cousins. Gender, faculty, parental income, and educational background influenced participants' attitudes.

Accelerated MEN2A in homozygous RET carriers in the context of consanguinity.

BACKGROUND: Homozygous mutations, 2 identical gene versions (alleles), 1 from each biological parent, are exceptional. Clinical descriptions of affected families, comprising few carriers only, are scattered throughout the literature, hindering evidence generation. METHODS: Included in this literature analysis were 5 RET families with ≥1 homozygous carrier and ≥3 heterozygous carriers per family. RESULTS: In consanguineous families with first-degree cousins, homozygotes presented with node-positive medullary thyroid cancer and pheochromocytoma in their mid-teens, whereas heterozygotes presented in their end-30s and early 40s. Homozygotes developed node-positive medullary thyroid cancer 27.4 years and pheochromocytoma 23 years earlier than heterozygotes. These age differences were smaller in the 15 families carrying founder mutation p.Leu666delinsAsnSer, whereas homozygotes developed node-positive medullary thyroid cancer in their mid-40s, 6 years earlier than heterozygotes in their early 50s. CONCLUSION: These results, limited in scope and size and modulated by extent of consanguinity, are consistent with moderate dose-response effects accelerating MEN2A development.

The first study of 3-M Syndrome in Jordan and Literature Review

The prevalence of 3-M syndrome remains unclear owing to its rarity and the limited number of reported cases in the medical literature. To date, approximately 100 cases of the disorder have been documented in MedlinePlus Genetics. Here, we present the first case study report from Jordan of a boy diagnosed with 3-M syndrome at 9 months of age via karyotyping. The patient exhibited distinct facial features, severe prenatal and postnatal growth retardation, and normal mental development. As rare genetic autosomal recessive mutations are common where consanguineous marriages are prevalent, raising awareness of such rare genetic diseases is critical. This paper aims to provide a case report on 3-M syndrome and a literature review. (AU)

DNA repair-related heritable photosensitivity syndromes: Mutation landscape in a multiethnic cohort of 17 multigenerational families with high degree of consanguinity.

Inherited photosensitivity syndromes are a heterogeneous group of genetic skin disorders with tremendous phenotypic variability, characterized by photosensitivity and defective DNA repair, especially nucleotide excision repair. A cohort of 17 Iranian families with heritable photosensitivity syndromes was evaluated to identify their genetic defect. The patients' DNA was analyzed with either whole-exome sequencing or RNA sequencing (RNA-Seq). The interpretations of the genomic results were guided by genome-wide homozygosity mapping. Haplotype analysis was performed for cases with recurrent mutations. RNA-Seq, in addition to mutation detection, was also utilized to confirm the pathogenicity. Thirteen sequence variants, including six previously unreported pathogenic variants, were disclosed in 17 Iranian families, with XPC as the most common mutated gene in 10 families (59%). In one patient, RNA-Seq, as a first-tier diagnostic approach, revealed a non-canonical homozygous germline variant: XPC:c.413-9 T > A. The Sashimi plot showed skipping of exon 4 with dramatic XPC down-expression. Haplotype analysis of XPC:c.2251-1 G>C and XPC:1243 C>T in four families showed common haplotypes of 1.7 Mb and 2.6 Mb, respectively, denoting a founder effect. Lastly, two extremely rare cases were presented in this report: a homozygous UVSSA:c .1990 C>T was disclosed, and ERCC2-related cerebro-oculo-facio-skeletal (COFS) syndrome with an early childhood death. A direct comparison of our data with the results of previously reported cohorts demonstrates the international mutation landscape of DNA repair-related photosensitivity disorders, although population-specific differences were observed.

Novel UBE3B mutations: report of eight patients with Kaufman oculocerebrofacial syndrome with additional clinical findings from a highly consanguineous population.

Biallelic mutations in UBE3B cause Kaufman oculocerebrofacial syndrome (KOS; OMIM 244450) with a wide range of clinical manifestations. In this study, we employed genetic analyses including homozygosity mapping, candidate gene sequencing, whole exome sequencing, and confirmatory Sanger sequencing on eight patients from three unrelated consanguineous families. Our analysis yielded three different novel variants in UBE3B : a missense substitution [NM_130466.4: c.2975C>T; (p.Pro992Leu)] in the HECT domain in family 1, a 3-bp deletion within exon 14 [c.1692_1694delCTC; (p.Ser565del)] leading to removal of a serine residue in family 2, and a splice donor site variant in intron eight of UBE3B (c.630 + 1G>T) in family 3. Blepharophimosis, telecanthus, ptosis, intellectual disability and abnormal lipid profile were similar to those found in previously reported KOS patients. Longitudinal follow-up revealed rather marfanoid body habitus of the patients in family 1. This study reports eight patients from Saudi Arabia with novel deleterious variants in UBE3B and adds to the phenotypic spectrum of KOS.

Mutational analysis in different genes underlying severe combined immunodeficiency in seven consanguineous Pakistani families.

BACKGROUND: Severe Combined Immunodeficiency (SCID) is an autosomal recessive inborn error of immunity (IEI) characterized by recurrent chest and gastrointestinal (GI) infections and in some cases associated with life-threatening disorders. METHODOLOGY AND RESULTS: This current study aims to unwind the molecular etiology of SCID and also extended the patients' phenotype associated with identified particular variants. Herein, we present 06 disease-causing variants identified in 07 SCID-patients in three different SCID related genes. Whole Exome Sequencing (WES) followed by Sanger Sequencing was employed to explore genetic variations. The results included identification of two previously reported heterozygous variants in homozygous form for the first time in RAG1gene [(p.Arg410Gln);(p.Arg737His)], followed by a recurrent variant (p.Trp959*) in RAG1, a novel variant in IL2RG (p.Asp48Lfs*24), a recurrent variant in IL2RG (p.Gly271Glu) and a recurrent variant in DCLRE1C (p.Arg191*) gene. CONCLUSION: To conclude, the immune-profiling and WES revealed two novel, two as homozygous state for the first time, and two recurrent disease causing variants contributing valuably to our existing knowledge of SCID.

Consanguinity in northwest Pakistan: evidence of temporal decline.

Pakistan has a high burden of hereditary and congenital anomalies and their incidence rate almost doubles against the background of parental consanguinity. Consanguineous unions (CU) are customary in Pakistan and deeply rooted socio-cultural norms favour CU. This study aimed to elucidate the determinants and temporal change in CU in four northwestern populations of Pakistan. In a cross-sectional study, data on marital union types, bio-demographic factors, and paternal consanguinity were collected from 6,323 ever-married individuals in four districts of northwest Pakistan: Haripur, Muzaffarabad, Mansehra, and Shangla. We used descriptive statistics and multivariable logistic regression analysis. The CU were calculated to be 55%, and inbreeding coefficient F (ICF) was estimated to be 0.029. Eight factors, including district, rural origin, age of husband, occupational group of husband, literacy of husband, parental consanguinity, exchange marriage, and extended family type, were found to be significant predictors of consanguinity in the multivariable logistic regression analysis. The rate of consanguinity decreased significantly in the younger age categories of individuals. The rate of CU was seen to be declining over time and in marriages that started 'before 1980' and 'after 2010', respectively, and there was a decline in ICF from 0.030 to 0.027. These analyses also showed that the literacy rate improved, the average age at marriage increased, and the frequency of exchange marriages decreased over time. This study employs a sizable first-hand dataset to demonstrate a lowering CU rate in northwest Pakistan. It is anticipated that the burden of inherited and congenital anomalies may likely to diminish in the study populations along with the fall in ICF.

Prevalence and socio-economic determinants of consanguineous marriages in Algeria according to Multiple Indicator Cluster Survey 2019 data (MICS6).

Consanguineous marriage is still a customary social phenomenon in Arab-Muslim communities. The aim of this study was to estimate the prevalence of consanguineous marriages in the Algerian population and to identify the socio-economic determinants associated with the practice of this form of union. This is a descriptive cross-sectional study included data for 21141 ever-married women aged 15-49 years, from the MICS6 Algeria (Multiple Indicator Cluster Survey database), conducted in 2019. Using a logistic regression model, we assessed the influence of socio-economic and geographical determinants on the practice of consanguineous marriages. The prevalence of consanguinity was 23.0% (95% CI: 22.4-23.6). According to multivariable binary logistic regression analysis, low level of education, early age at marriage (15-19; 20-30 years), rural area of residence, all geographical regions except the north-western territorial programming space, economic activity, and the lowest wealth index were the main determinants that assist in the prevalence of high rates of consanguineous marriages in Algeria. Considering these explanatory variables could help national health policy decision-makers to create and implement national preventive action plans that are intended alter behaviors attitudes toward preference of consanguineous marriages and, thus, reduce the burden of genetic disorders or congenital abnormalities associated with consanguinity.

Second report of TEDC1-related microcephaly caused by a novel biallelic mutation in an Iranian consanguineous family.

BACKGROUND: Primary autosomal recessive microcephaly (MCPH) is a rare developmental disorder characterized by cognitive impairment, delayed neurodevelopment, and reduced brain size. It is a genetically heterogeneous condition, and several genes have been identified as associated with MCPH. METHODS AND RESULTS: In this study, we utilized whole-exome sequencing (WES) to identify disease-causing variations in two brothers from an Iranian family affected by MCPH, who had consanguineous parents. In the patients, we detected a novel homozygous missense mutation (c.806A > G, p.Gln269Arg) in the TEDC1 gene in one of the patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from parents. The identified variant was evaluated for its pathogenicity and novelty using various databases. Additionally, bioinformatics tools were employed to predict the three-dimensional structure of the mutant TEDC1 protein. CONCLUSIONS: This study presents the second documented report of a mutation in the TEDC1 gene associated with MCPH. The identification of this novel biallelic mutation as a causative factor for MCPH in the proband further underscores the utility of genetic testing techniques, such as WES, as reliable diagnostic tools for individuals with this condition.

A novel biallelic 19-bp deletion in the IL10RB gene caused infant-onset inflammatory bowel disease in a consanguineous family: a molecular docking simulation study and literature review.

BACKGROUND: Infantile-onset inflammatory bowel disease (IOIBD) is a gastrointestinal inflammatory condition often associated with monogenic disorders and is frequently caused by Interleukin-10 deficiencies. This study aimed to identify the mutation responsible for IBD in an 8-year-old patient from an Iranian family with consanguineous parents. METHODS: Whole-exome sequencing (WES) was employed to identify disease-causing variations. Furthermore, we utilized integrated experimental data of HADDOCK molecular docking platform, including NMR spectroscopy, to characterize the mutant protein and elucidate the underlying functional mechanism of the identified mutation's pathogenicity. RESULTS: Our findings revealed a novel 19-bp deletion mutation (c.25_43del, p.Leu9CysfsTer15) in the IL10RB gene. Sanger sequencing confirmed that this variant was inherited in homozygous state within this family, marking the first mutation identified in exon 1 of this gene. Molecular docking simulation demonstrated that the mutant form of IL10RB exhibited reduced affinity for binding to the Interleukin-10 ligand, leading to disruptions in downstream cellular signaling pathways. CONCLUSIONS: The identification of this novel genetic variant as a causative factor for IOIBD highlights the clinical value of utilizing genetic testing, such as WES, as a reliable diagnostic approach for patients affected by this condition.

Consanguineous marriages increase the incidence of recurrent tuberculosis: Evidence from whole exome sequencing.

BACKGROUND: In this study, we have identified multiple mutations in the IL-12R1 gene among Pakistani patients who have inherited them through consanguineous marriages. These patients have experienced severe Bacille-Calmette-Guérin (BCG) infection as well as recurrent tuberculosis. We will demonstrate the pivotal role of interleukin (IL)-12/interferon (IFN)-γ axis in the regulation of mycobacterial diseases. METHODOLOGY: First, we checked the patients' medical records, and then afterward, we assessed interferon-gamma (IFN-γ) production through ELISA. Following that, DNA was extracted to investigate IL-12/IFN- abnormalities. Whole exome sequencing was conducted through Sanger sequencing. Secretory cytokine levels were compared from healthy control of the same age groups and they were found to be considerably less in the disease cohort. To evaluate the probable functional impact of these alterations, an in silico study was performed. RESULTS: The study found that the patients' PBMCs produced considerably less IFN-γ than expected. Analysis using flow cytometry showed that activated T cells lacked surface expression of IL-12Rß1. Exon 7 of the IL-12Rß1 gene, which encodes a portion of the cytokine binding region (CBR), and exon 10, which encodes the fibronectin-type III (FNIII) domain, were found to have the mutations c.641 A > G; p.Q214R and c.1094 T > C; p.M365T, respectively. In silico analysis showed that these mutations likely to have a deleterious effect on protein function. CONCLUSION: Our findings indicate the significant contribution of the IL-12/IFN-γ is in combating infections due to mycobacterium. Among Pakistani patients born to consanguineous marriages, the identified mutations in the IL-12Rß-1 gene provide insights into the genetic basis of severe BCG infections and recurrent tuberculosis. The study highlights the potential utility of newborn screening in regions with mandatory BCG vaccination, enabling early detection and intervention for primary immunodeficiencies associated with mycobacterial infections. Moreover, the study suggests at the potential role of other related genes such as IL-23Rß1, TYK2, or JAK2 in IFN-γ production, warranting further investigation.

Investigating the effects of a single ASPM variant (c.8508_8509) on brain architecture among siblings in a consanguineous Pakistani family.

BACKGROUND: Autosomal Recessive Primary Microcephaly (MCPH) is a rare, neurodevelopmental disorder associated with mild to severe mental retardation. It is characterized by reduced cerebral cortex that ultimately leads to reduction in skull size less than - 3 S.D below the mean for normal individuals having same age and sex. Till date, 30 known loci have been reported for MCPH. METHODS: In the present study, Sanger sequencing was performed followed by linkage analysis to validate the mutation in ASPM gene of the consanguineous Pakistani clans. Bioinformatics tools were also used to confirm the pathogenicity of the diseased variant in the gene. MRI scan was used to compare the brain structure of both the affected individuals (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023). RESULTS: Our study described a consanguineous family with two patients with a known ASPM (MCPH5) variant c.8508_8509delGA causing a frameshift mutation in exon 18 which located in calmodulin-binding IQ domain of the ASPM protein. The salient feature of this study is that a single variant led to significantly distinct changes in the architecture of brain of both siblings which is further confirmed by MRI results. The computation analysis showed that the change in the conservation of this residue cause this variant highly pathogenic. Carrier screening and genetic counselling were also remarkable features of this study (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023). CONCLUSION: This study explores the extraordinary influence of a single ASPM variant on divergent brain structure in consanguineous siblings and enable us to reduce the incidence of further microcephalic cases in this Pakistani family (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023).

Stepwise genetic approach for the diagnosis of primary ciliary dyskinesia in highly consanguineous populations.

BACKGROUND: The American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia (PCD) consider the presence of a bi-allelic pathogenic variant confirmatory for the diagnosis of PCD, with genetic testing recommended when other confirmatory diagnostic tests are less accessible. We present our experience with genetic testing as first line with a proposed algorithm for high consanguinity populations. METHODS: Patients with a suspected diagnosis of PCD underwent genetic testing according to a diagnostic algorithm composed of three steps: (1) patients with a previously known causative familial/Bedouin tribal pathogenic variant completed direct testing for a single variant; (2) if the initial test was negative or there was no known pathogenic variant, a PCD genetic panel was completed; (3) if the panel was negative, whole exome sequencing (WES) was completed. RESULTS: Since the implementation of the protocol, diagnosis was confirmed by genetic testing in 21 patients. The majority of them were of Bedouin origin (81%) and had a positive history of consanguinity (65%). Nine patients (43%) had a sibling with a confirmed diagnosis. Most patients (15/21, 71%) were diagnosed by direct pathogenic variant testing and the remainder by genetic panel (19%) and WES (10%). Disease-causing variants were found in nine genes, with DNAL1 (24%) and DNAAF3, DNAAF5, ZMYND10 (14% each) as the most prevalent ones. CONCLUSIONS: In highly consanguineous regions, a stepwise genetic testing approach is recommended. This approach may be particularly useful in areas where the ability to obtain confirmatory diagnostic tests through other modalities is less accessible.

Modeling the effects of consanguinity on autosomal and X-chromosomal runs of homozygosity and identity-by-descent sharing.

Runs of homozygosity (ROH) and identity-by-descent (IBD) sharing can be studied in diploid coalescent models by noting that ROH and IBD-sharing at a genomic site are predicted to be inversely related to coalescence times-which in turn can be mathematically obtained in terms of parameters describing consanguinity rates. Comparing autosomal and X-chromosomal coalescent models, we consider ROH and IBD-sharing in relation to consanguinity that proceeds via multiple forms of first-cousin mating. We predict that across populations with different levels of consanguinity, (1) in a manner that is qualitatively parallel to the increase of autosomal IBD-sharing with autosomal ROH, X-chromosomal IBD-sharing increases with X-chromosomal ROH, owing to the dependence of both quantities on consanguinity levels; (2) even in the absence of consanguinity, X-chromosomal ROH and IBD-sharing levels exceed corresponding values for the autosomes, owing to the smaller population size and lower coalescence time for the X chromosome than for autosomes; (3) with matrilateral consanguinity, the relative increase in ROH and IBD-sharing on the X chromosome compared to the autosomes is greater than in the absence of consanguinity. Examining genome-wide SNPs in human populations for which consanguinity levels have been estimated, we find that autosomal and X-chromosomal ROH and IBD-sharing levels generally accord with the predictions. We find that each 1% increase in autosomal ROH is associated with an increase of 2.1% in X-chromosomal ROH, and each 1% increase in autosomal IBD-sharing is associated with an increase of 1.6% in X-chromosomal IBD-sharing. For each calculation, particularly for ROH, the estimate is reasonably close to the increase of 2% predicted by the population-size difference between autosomes and X chromosomes. The results support the utility of coalescent models for understanding patterns of genomic sharing and their dependence on sex-biased processes.

Understanding recessive disease risk in multi-ethnic populations with different degrees of consanguinity.

Population medical genetics aims at translating clinically relevant findings from recent studies of large cohorts into healthcare for individuals. Genetic counseling concerning reproductive risks and options is still mainly based on family history, and consanguinity is viewed to increase the risk for recessive diseases regardless of the demographics. However, in an increasingly multi-ethnic society with diverse approaches to partner selection, healthcare professionals should also sharpen their intuition for the influence of different mating schemes in non-equilibrium dynamics. We, therefore, revisited the so-called out-of-Africa model and studied in forward simulations with discrete and not overlapping generations the effect of inbreeding on the average number of recessive lethals in the genome. We were able to reproduce in both frameworks the drop in the incidence of recessive disorders, which is a transient phenomenon during and after the growth phase of a population, and therefore showed their equivalence. With the simulation frameworks, we also provide the means to study and visualize the effect of different kin sizes and mating schemes on these parameters for educational purposes.

Paediatric diabetes subtypes in a consanguineous population: a single-centre cohort study from Kurdistan, Iraq.

AIMS/HYPOTHESIS: Monogenic diabetes is estimated to account for 1-6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined. In this single-centre study we aimed to evaluate diabetes subtypes, obtain the consanguinity rate and study the genetic background of individuals with syndromic and neonatal diabetes in a population with a high rate of consanguinity. METHODS: Data collection was carried out cross-sectionally in November 2021 at the paediatric diabetic clinic, Dr Jamal Ahmad Rashed Hospital, in Sulaimani, Kurdistan, Iraq. At the time of data collection, 754 individuals with diabetes (381 boys) aged up to 16 years were registered. Relevant participant data was obtained from patient files. Consanguinity status was known in 735 (97.5%) participants. Furthermore, 12 families of children with neonatal diabetes and seven families of children with syndromic diabetes consented to genetic testing by next-generation sequencing. Prioritised variants were evaluated using the American College of Medical Genetics and Genomics guidelines and confirmed by Sanger sequencing. RESULTS: A total of 269 of 735 participants (36.5%) with known consanguinity status were offspring of consanguineous families. An overwhelming majority of participants (714/754, 94.7%) had clinically defined type 1 diabetes (35% of them were born to consanguineous parents), whereas only eight (1.1%) had type 2 diabetes (38% consanguineous). Fourteen (1.9%) had neonatal diabetes (50% consanguineous), seven (0.9%) had syndromic diabetes (100% consanguineous) and 11 (1.5%) had clinically defined MODY (18% consanguineous). We found that consanguinity was significantly associated with syndromic diabetes (p=0.0023) but not with any other diabetes subtype. The genetic cause was elucidated in ten of 12 participants with neonatal diabetes who consented to genetic testing (homozygous variants in GLIS3 [sibling pair], PTF1A and ZNF808 and heterozygous variants in ABCC8 and INS) and four of seven participants with syndromic diabetes (homozygous variants in INSR, SLC29A3 and WFS1 [sibling pair]). In addition, a participant referred as syndromic diabetes was diagnosed with mucolipidosis gamma and probably has type 2 diabetes. CONCLUSIONS/INTERPRETATION: This unique single-centre study confirms that, even in a highly consanguineous population, clinically defined type 1 diabetes is the prevailing paediatric diabetes subtype. Furthermore, a pathogenic cause of monogenic diabetes was identified in 83% of tested participants with neonatal diabetes and 57% of participants with syndromic diabetes, with most variants being homozygous. Causative genes in our consanguineous participants were markedly different from genes reported from non-consanguineous populations and also from those reported in other consanguineous populations. To correctly diagnose syndromic diabetes in consanguineous populations, it may be necessary to re-evaluate diagnostic criteria and include additional phenotypic features such as short stature and hepatosplenomegaly.