PURPOSE: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.

• MeSH
• Algorithms MeSH
• Child MeSH
• Genetic Testing * methods   MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation genetics   MeSH
• Dwarfism genetics   diagnosis   MeSH
• Consanguinity * MeSH
• Growth Disorders genetics   diagnosis   MeSH
• Child, Preschool MeSH
• Pedigree MeSH
• Exome Sequencing methods   MeSH
• Body Height genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Iraq MeSH

INTRODUCTION: Pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID) syndrome is a rare disease, and part of the cluster histiocytosis-lymphadenopathy plus syndrome (H syndrome), which is associated with mutations in the SLC29A3 gene. Patients with PHID show clinical features of H syndrome but also have insulin-dependent diabetes mellitus. The PHID has previously been described as predominantly in absence of pancreatic autoantibodies. Case Series Presentation: Through an open call in two international diabetes registers, clinical and genetic characteristics of 7 PHID patients in 6 treatment centres were collected after informed consent. All of them had consanguinity in their families, and their origins were located in North-African and Middle Eastern regions. Four out of 7 patients had at least one positive pancreatic autoantibody. DISCUSSION AND CONCLUSION: Our case series reveals that PHID exhibits a wide range of clinical symptoms and signs. When consanguinity is present in a patient with newly diagnosed diabetes, and/or if other atypical symptoms such as dysmorphic features, skin lesions, haematological abnormalities, and developmental delay are present, threshold for genetic analysis should be low. Moreover, the presence of autoantibodies should not withhold genetic testing as our case series contradicts the previous observation of predominant autoantibody absence in PHID.

• MeSH
• Autoantibodies blood   immunology   MeSH
• Diabetes Mellitus, Type 1 * genetics   complications   MeSH
• Child MeSH
• Hypertrichosis * genetics   MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation MeSH
• Consanguinity MeSH
• Child, Preschool MeSH
• Nucleoside Transport Proteins genetics   MeSH
• Syndrome MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

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.

• MeSH
• Diabetes Mellitus, Type 1 * epidemiology   genetics   MeSH
• Diabetes Mellitus, Type 2 * epidemiology   genetics   diagnosis   MeSH
• Child MeSH
• Cohort Studies MeSH
• Humans MeSH
• Mutation genetics   MeSH
• Infant, Newborn, Diseases * genetics   MeSH
• Infant, Newborn MeSH
• Consanguinity MeSH
• Nucleoside Transport Proteins genetics   MeSH
• Aged MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Iraq MeSH

BACKGROUND: Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare childhood cancer predisposition syndrome associated with a broad spectrum of malignancies, including non-Hodgkin lymphomas (NHL). Most patients die due to cancer before the age of 20 years. Limited data exist on CMMRD-associated lymphomas and their outcome. METHODS: We conducted a retrospective study including all CMMRD-associated NHL patients registered before 2020 in the European and North American databases or reported by members of the European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL). Events considered to define event-free survival included relapse/progression, second malignancy (SML), or death, whichever occurred first. FINDINGS: The analysis included 74 patients, with 20 having multiple metachronous NHL. The median age at diagnosis was 9.4 years. Previous malignancies were reported in 36% of the patients, café au lait spots in 96%, and consanguinity in 54%. The initial lymphoma subtypes were 53 T-cell lymphoblastic lymphomas (T-LBL), four B-lymphoblastic lymphomas, and 17 mature B-cell non-Hodgkin lymphoma (B-NHL). All patients were treated with curative intent, with current chemotherapy regimens adapted to their subtype. The median follow-up was 8.7 years. After the first lymphoma, the 5-year event-free and overall survival rates were, respectively, 23.5% [95% confidence interval (CI): 14.9-35.1] and 61.5% [95% CI: 49.6-72.1]. The 5-year cumulative risk of progression/relapse, SML or death as a first event was 20.8%, 52.9%, and 2.7%. INTERPRETATION: Standard treatments for sporadic NHL are effective in most CMMRD-associated NHL cases, but multiple malignancies, including lymphomas, impair prognosis. Future strategies should evaluate the potential of less genotoxic therapies, including immunotherapy, in preventing SMLs while maintaining effective control of NHL.

• MeSH
• Neoplastic Syndromes, Hereditary genetics   mortality   MeSH
• Child MeSH
• Adult MeSH
• Infant MeSH
• Colorectal Neoplasms MeSH
• Humans MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Young Adult MeSH
• Brain Neoplasms MeSH
• Follow-Up Studies MeSH
• Lymphoma, Non-Hodgkin * mortality   genetics   epidemiology   MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Retrospective Studies MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: Given Iran's recent shift towards pronatalist population policies, concerns have arisen regarding the potential increase in abortion rates. This review study examines the trends of (medical), intentional (illegal), and spontaneous abortions in Iran over the past two decades, as well as the factors that have contributed to these trends. METHODS: This paper reviewed research articles published between 2005 and 2022 on abortion in Iran. The study employed the PRISMA checklist for systematic reviews. Articles were searched from international (Google Scholar, PubMed, Science Direct, and Web of Science) and national databases (Magiran, Medlib, SID). Once the eligibility criteria were applied, 42 records were included from the initial 349 records. RESULTS: Abortion is influenced by a variety of socioeconomic and cultural factors and the availability of family planning services. Factors that contribute to unintended pregnancy include attitudes toward abortion, knowledge about reproductive health, access to reproductive health services, and fertility desires, among others. In addition to health and medical factors, consanguineous marriage plays an important role in spontaneous and therapeutic abortion. A higher number of illegal abortions were reported by women from more privileged socioeconomic classes. In comparison, a higher number of medical and spontaneous abortions were reported by women from less privileged socioeconomic classes. CONCLUSION: Iranian policymakers are concerned about the declining fertility rate and have turned to pronatalist policies. From a demographic standpoint, this seems to be a reasonable approach. However, the new population policies, particularly, the Family Protection and Young Population Law, along with creating limitations in access to reproductive health services and prenatal screening tests as well as stricter abortion law could potentially lead to an increase in various types of abortions and their associated consequences.

• MeSH
• Abortion, Induced * statistics & numerical data   legislation & jurisprudence   trends   MeSH
• Humans MeSH
• Abortion, Illegal statistics & numerical data   MeSH
• Abortion, Spontaneous epidemiology   MeSH
• Socioeconomic Factors MeSH
• Pregnancy MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Systematic Review MeSH
• Geographicals
• Iran MeSH

BACKGROUND: The Roma population is a genetically isolated population with a shared origin, totaling between 10 to 14 million individuals worldwide, stemming from a limited number of “genetic founders”. Roma individuals exhibit specific hereditary diseases, often stemming from recessive genetic variants due to a higher degree of consanguinity, with recent molecular-genetic investigations shedding light on several conditions prevalent within the Czech Roma population. However, an overview of stomatological issues in diagnosing such diseases proves challenging, leading to frequent underdiagnosis or misdiagnosis. METHODS: The contribution monitors the clinical description, typical symptoms and treatment options including dental abnormalities in rare genetic diseases in the Roma population which are treated in ERN CRANIO centre at Motol University Hospital in Prague. RESULTS: Our research provides examples of autosomal recessive diseases, which can be molecularly confirmed, and prevalent within the Roma community. These include congenital cataract syndrome, facial dysmorphism and demyelinating neuropathy, non-syndromic prelingual e.g. deafness with GJB2 gene impairment, and myasthenic syndrome. CONCLUSION: Our report aimed to provide a systematic review of dental phenotypes which can relate to Czech Roma’s rare genetic disorders therapy including dental treatment. Understanding is important for preventing unterdiagnosis or treatment for the patients affected review of observed (Fig. 6, Ref. 27).

• MeSH
• Tooth Abnormalities * genetics   diagnosis   ethnology   MeSH
• Humans MeSH
• Roma * genetics   MeSH
• Syndrome MeSH
• Rare Diseases genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Systematic Review MeSH
• Geographicals
• Czech Republic MeSH

Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies.

• Publication type
• Journal Article MeSH

BACKGROUND: Cystic fibrosis (CF) is a rare multi-systemic recessive disorder. The spectrum and the frequencies of CFTR mutations causing CF vary amongst different populations in Europe and the Middle East. In this study, we characterised the distribution of CF-causing mutations (i.e. pathogenic variants in the CFTR gene) in a representative CF cohort from the Kingdom of Bahrain based on a three-decade-long analysis at a single tertiary centre. We aim to improve CF genetic diagnostics, introduce of CF neonatal screening and provide CFTR modulator therapy (CFTRm). METHODS: CFTR genotyping and associated clinical information were drawn from a longitudinal cohort. We sequenced 56 people with CF (pwCF) that had one or both CFTR mutations unidentified and carried out comprehensive bioinformatic- and family-based segregation analyses of detected variants, including genotype-phenotype correlations and disease incidence estimates. The study methodology could serve as a basis for other non-European CF populations with a high degree of consanguinity. RESULTS: Altogether 18 CF-causing mutations were identified, 15 of which were not previously detected in Bahrain, accounting for close to 100% of all population-specific alleles. The most common alleles comprise c.1911delG [2043delG; 22.8%], c.2988+1G > A [3120+1G>A; 16.3%], c.2989-1G>A [3121-1G>A; 14.1%], c.3909C>G [N1303K; 13.0%], and c.1521_1523delCTT [p.PheF508del; 7.6%]. Although the proportion of 1st cousin marriages has decreased to 50%, the frequency of homozygosity in our pwCF is 67.4%, thereby indicating that CF still occurs in large, often related, families. pwCF in Bahrain present with faltering growth, pancreatic insufficiency and classical sino-pulmonary manifestations. Interestingly, two pwCF also suffer from sickle cell disease. The estimated incidence of CF in Bahrain based on data from the last three decades is 1 in 9,880 live births. CONCLUSION: The most commonCF-causing mutations in Bahraini pwCF were identified, enabling more precise diagnosis, introduction of two-tier neonatal screening and fostering administration of CFTRm.

• MeSH
• Alleles MeSH
• Cystic Fibrosis * genetics   MeSH
• Child MeSH
• Adult MeSH
• Genetic Association Studies methods   MeSH
• Genotype MeSH
• Cohort Studies MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation * MeSH
• Infant, Newborn MeSH
• Neonatal Screening MeSH
• Child, Preschool MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator * genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Bahrain MeSH

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

• MeSH
• Neoplastic Syndromes, Hereditary * genetics   therapy   MeSH
• Child MeSH
• DNA-Binding Proteins * MeSH
• Adult MeSH
• MutS Homolog 2 Protein genetics   MeSH
• Incidence MeSH
• Colorectal Neoplasms genetics   pathology   mortality   MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation MeSH
• MutL Protein Homolog 1 genetics   MeSH
• Brain Neoplasms genetics   therapy   mortality   pathology   epidemiology   MeSH
• DNA Mismatch Repair MeSH
• Child, Preschool MeSH
• Cross-Sectional Studies MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: The Roma population is a genetically isolated population with a shared origin, totaling between 10 to 14 million individuals worldwide, stemming from a limited number of "genetic founders". Roma individuals exhibit specific hereditary diseases, often stemming from recessive genetic variants due to a higher degree of consanguinity, with recent molecular-genetic investigations shedding light on several conditions prevalent within the Czech Roma population. However, an overview of stomatological issues in diagnosing such diseases proves challenging, leading to frequent underdiagnosis or misdiagnosis. METHODS: The contribution monitors the clinical description, typical symptoms and treatment options including dental abnormalities in rare genetic diseases in the Roma population which are treated in ERN CRANIO centre at Motol University Hospital in Prague. RESULTS: Our research provides examples of autosomal recessive diseases, which can be molecularly confirmed, and prevalent within the Roma community. These include congenital cataract syndrome, facial dysmorphism and demyelinating neuropathy, non-syndromic prelingual e.g. deafness with GJB2 gene impairment, and myasthenic syndrome. CONCLUSION: Our report aimed to provide a systematic review of dental phenotypes which can relate to Czech Roma's rare genetic disorders therapy including dental treatment. Understanding is important for preventing unterdiagnosis or treatment for the patients affected review of observed (Fig. 6, Ref. 27).

• MeSH
• Tooth Abnormalities * genetics   diagnosis   ethnology   MeSH
• Humans MeSH
• Roma * genetics   MeSH
• Syndrome MeSH
• Rare Diseases genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Systematic Review MeSH
• Geographicals
• Czech Republic MeSH