OBJECTIVE: To investigate the clinical features, ALDH5A1 gene variations, treatment, and prognosis of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency.
METHODS: This retrospective study evaluated the findings in 13 Chinese patients with SSADH deficiency admitted to the Pediatric Department of Peking University First Hospital from September 2013 to September 2023.
RESULTS: Thirteen patients (seven male and six female patients; two sibling sisters) had the symptoms aged from 1 month to 1 year. Their urine 4-hydroxybutyrate acid levels were elevated and were accompanied by mildly increased serum lactate levels. Brain magnetic resonance imaging (MRI) showed symmetric abnormal signals in both sides of the globus pallidus and other areas. All 13 patients had psychomotor retardation, with seven showing epileptic seizures. Among the 18 variants of the ALDH5A1 gene identified in these 13 patients, six were previously reported, while 12 were novel variants. Among the 12 novel variants, three (c.85_116del, c.206_222dup, c.762C > G) were pathogenic variants; five (c.427delA, c.515G > A, c.637C > T, c.755G > T, c.1274T > C) were likely pathogenic; and the remaining four (c.454G > C, c.479C > T, c.1480G > A, c.1501G > C) were variants of uncertain significance. The patients received drugs such as L-carnitine, vigabatrin, and taurine, along with symptomatic treatment. Their urine 4-hydroxybutyric acid levels showed variable degrees of reduction.
CONCLUSIONS: A cohort of 13 cases with early-onset SSADH deficiency was analyzed. Onset of symptoms occurred from 1 month to 1 year of age. Twelve novel variants of the ALDH5A1 gene were identified.

UNASSIGNED: Familial hemophagocytic lymphohistiocytosis (FHLH) is an inherited life-threatening disease. Five types are identified, with the addition of congenital immunodeficiency syndromes in which HLH is a typical manifestation. The literature on this disease is very scarce in the Middle East, with only a few scattered reports.
UNASSIGNED: We report detailed demographic, clinical, and genomic data from 28 patients diagnosed with primary and familial HLH over the last decade in Qatar. An evaluation was performed of allele frequencies of deleterious variants from 12 primary and familial HLH causative genes on the Qatar Genome Programme (QGP) cohort of 14,669 Qatari individuals.
UNASSIGNED: The genetic diagnosis was obtained in 15 patients, and four novel mutations in Perforin 1 (PRF1), UNC13D, LYST, and RAB27A genes were found. We identified 22,945 low/high/moderate/modifier impact variants significantly enriched in the QGP in those 12 genes. The variants rs1271079313 in PRF1 and rs753966933 in RAB27A found in our patient cohort were significantly more prevalent in the QGP compared to the Genome Aggregation Database (gnomAD) database, with a high carrier frequency in the Qatari population.
UNASSIGNED: We established the first primary and familial HLH Registry in the Gulf Region and identified novel possibly pathogenic variants present at higher frequency in the Qatari population, which could be used for screening purposes. Raising awareness about primary and familial HLH and implementing screening activities in the Qatari highly inbred population could stem into more comprehensive premarital and prenatal evaluations and faster diagnosis.

OBJECTIVE: Dentinogenesis imperfecta (DI) is an inherited dentin defect and may be isolated or associated with disorders such as osteogenesis imperfecta, odontochondrodysplasia Ehler-Danlos and others. Isolated DI is caused mainly by pathogenic variants in DSPP gene and around 50 different variants have been described in this gene. Herein, we report on 19 patients from two unrelated Egyptian families with isolated DI. Additionally, we focused on genetic counselling of the two families.
METHODS: The patients were examined clinically and dentally. Panoramic X-rays were done to some patients. Whole exome sequencing (WES) and Sanger sequencing were used.
RESULTS: WES revealed two new nonsense variants in DSPP gene, c.288T > A (p.Tyr96Ter) and c.255G > A (p.Trp85Ter). Segregation analysis by Sanger sequencing confirmed the presence of the first variant in all affected members of Family 1 while the second variant was confirmed to be de novo in the patient of Family 2.
CONCLUSIONS: Our study extends the number of DSPP pathogenic variants and strengthens the fact that DSPP is the most common DI causative gene irrespective of patients\' ethnicity. In addition, we provide insights on genetic counseling issues in patients with inherited DSPP variants taking into consideration the variable religion, culture and laws in our society.

UNASSIGNED: Molecular diagnosis of cystic fibrosis (CF) is challenging in Mexico due to the population\'s high genetic heterogeneity. To date, 46 pathogenic variants (PVs) have been reported, yielding a detection rate of 77%. We updated the spectrum and frequency of PVs responsible for this disease in mexican patients.
UNASSIGNED: We extracted genomic DNA from peripheral blood lymphocytes obtained from 297 CF patients and their parents. First, we analyzed the five most frequent PVs in the Mexican population using PCR-mediated site-directed mutagenesis. In patients with at least one identified allele, CFTR sequencing was performed using next-generation sequencing tools and multiplex ligation-dependent probe amplification. For variants not previously classified as pathogenic, we used a combination of in silico prediction, CFTR modeling, and clinical characteristics to determine a genotype-phenotype correlation.
UNASSIGNED: We identified 95 PVs, increasing the detection rate to 87.04%. The most frequent variants were p.(PheF508del) (42.7%), followed by p.(Gly542*) (5.6%), p.(Ser945Leu) (2.9%), p.(Trp1204*) and p.(Ser549Asn) (2.5%), and CFTRdel25-26 and p.(Asn386Ilefs*3) (2.3%). The remaining variants had frequencies of <2.0%, and some were exclusive to one family. We identified 10 novel PVs localized in different exons (frequency range: 0.1-0.8%), all of which produced structural changes, deletions, or duplications in different domains of the protein, resulting in dysfunctional ion flow. The use of different in silico software and American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) criteria allowed us to assume that all of these PVs were pathogenic, causing a severe phenotype.
UNASSIGNED: In a highly heterogeneous population, combinations of different tools are needed to identify the variants responsible for CF and enable the establishment of appropriate strategies for CF diagnosis, prevention, and treatment.

BACKGROUND: SLCO1B1 plays an important role in mediating hepatic clearance of many different drugs including statins, angiotensin-converting enzyme inhibitors, chemotherapeutic agents and antibiotics. Several variants in SLCO1B1 have been shown to have a clinically significant impact, in relation to efficacy of these medications. This study provides a comprehensive overview of SLCO1B1 variation in Saudi individuals, one of the largest Arab populations in the Middle East.
METHODS: The dataset of 11,889 (9,961 exomes and 1,928 pharmacogenetic gene panel) Saudi nationals, was used to determine the presence and frequencies of SLCO1B1 variants, as described by the Clinical Pharmacogenetic Implementation Consortium (CPIC).
RESULTS: We identified 141 previously described SNPs, of which rs2306283 (50%) and rs4149056 (28%), were the most common. In addition, we observed six alleles [*15 (24.7%) followed by *20 (8.04%), *14 (5.86%), *5 (3.84%), *31 (0.21%) and *9 (0.03%)] predicted to be clinically actionable. Allele diplotype to phenotype conversion revealed 41 OATP1B1 diplotypes. We estimated the burden of rare, and novel predicted deleterious variants, resulting from 17 such alterations.
CONCLUSIONS: The data we present, from one of the largest Arab cohorts studied to date, provides the most comprehensive overview of SLCO1B1 variants, and the subsequent OATP1B1 activity of this ethnic group, which thus far remains relatively underrepresented in available international genomic databases. We believe that the presented data provides a basis for further clinical investigations and the application of personalized statin drug therapy guidance in Arabs.

UNASSIGNED: Autosomal recessive intellectual developmental disorder-3 is caused by homozygous or compound heterozygous mutations in the CC2D1A gene. The disorder is characterized by intellectual disability (ID) and autism spectrum disorder (ASD). To date, 39 patients from 17 families with CC2D1A -related disorders have been reported worldwide, in whom only six pathogenic or likely pathogenic loss-of-function variants and three variants of uncertain significance (VUS) in the CC2D1A gene have been identified in these patients.
UNASSIGNED: We described a patient with ID from a non-consanguineous Chinese family and whole-exome sequencing (WES) was used to identify the causative gene.
UNASSIGNED: The patient presented with severe ID and ASD, speech impairment, motor delay, hypotonia, slight facial anomalies, and finger deformities. Threatened abortion and abnormal fetal movements occurred during pregnancy with the proband but not his older healthy sister. WES analysis identified a homozygous nonsense variant, c.736C > T (p.Gln246Ter), in the CC2D1A gene. In addition, six novel likely pathogenic CC2D1A variants were identified by a retrospective review of the in-house database.
UNASSIGNED: This study expands the genetic and clinical spectra of CC2D1A-associated disorders, and may aid in increasing awareness of this rare condition. Our findings have provided new insights into the clinical heterogeneity of the disease and further phenotype-genotype correlation, which could help to offer scope for more accurate genetic testing and counseling to affected families.

UNASSIGNED: Alport syndrome (AS) is an inherited, rare, progressive kidney disease that affects the eye and ear physiology. Pathogenic variants of COL4A5 account for 85% of all cases, while COL4A3 and COL4A4 account for the remaining 15%.
UNASSIGNED: Targeted next-generation sequencing of the COL4A3, COL4A4, and COL4A5 genes was performed in 125 Turkish patients with AS. The patients were compared to 45 controls and open-access population data.
UNASSIGNED: The incidence of AS variants in patients was found as 21.6%. 27 variants were identified as pathogenic/likely pathogenic, 28 as variant of uncertain significance, and 52 as benign/likely benign. We also found 31 novel variants (14 in COL4A3, 6 in COL4A4, and 11 in COL4A5) of which 27 were classified as pathogenic/likely pathogenic. Pathogenic/likely Pathogenic variants were most commonly found in the COL4A5 gene, consistent with the literature. This study contributed novel variants associated with AS to the literature.
UNASSIGNED: Genetic testing is a crucial part for the diagnosis and management of AS. Studies on the genetic etiology of AS are limited for the Turkish population. We believe that this study will contribute to the literature and the clinical decision-making process of patients with AS and emphasize the importance of genetic counseling.

Kleefstra syndrome (KLEFS) refers to a rare inherited neurodevelopmental disorder characterized by intellectual disability (ID), language and motor delays, behavioral abnormalities, abnormal facial appearance, and other variable clinical features. KLEFS is subdivided into two subtypes: Kleefstra syndrome-1 (KLEFS1, OMIM: 610253), caused by a heterozygous microdeletion encompassing the Euchromatic Histone Lysine Methyltransferase 1 (EHMT1) gene on chromosome 9q34.3 or pathogenic variants in the EHMT1 gene, and Kleefstra syndrome-2 (KLEFS2, OMIM: 617768), caused by pathogenic variants in the KMT2C gene. More than 100 cases of KLEFS1 have been reported with pathogenic variants in the EHMT1 gene. However, only 13 patients with KLEFS2 have been reported to date. In the present study, five unrelated Chinese patients were diagnosed with KLEFS2 caused by KMT2C variants through whole-exome sequencing (WES). We identified five different variants of the KMT2C gene in these patients: c.9166C>T (p.Gln3056*), c.9232_9247delCAGCGATCAGAACCGT (p.Gln3078fs*13), c.5068dupA (p.Arg1690fs*10), c.10815_10819delAAGAA (p.Lys3605fs*7), and c.6911_6912insA (p.Met2304fs*8). All five patients had a clinical profile similar to that of patients with KLEFS2. To analyze the correlation between the genotype and phenotype of KLEFS2, we examined 18 variants and their associated phenotypes in 18 patients with KLEFS2. Patients carrying KMT2C variants presented with a wide range of phenotypic defects and an extremely variable phenotype. We concluded that the core phenotypes associated with KMT2C variants were intellectual disability, facial dysmorphisms, language and motor delays, behavioral abnormalities, hypotonia, short stature, and weight loss. Additionally, sex may be one factor influencing the outcome. Our findings expand the phenotypic and genetic spectrum of KLEFS2 and help to clarify the genotype-phenotype correlation.

UNASSIGNED: Alport syndrome (AS) is a hereditary, progressive kidney disease characterized by structural abnormalities and dysfunction of the glomerular basement membrane (GBM). AS is classified as X-linked, autosomal, and digenic. The number of cases of digenic AS has increased, but the genotype-phenotype correlation of patient with digenic AS is still unclear. Here, we present a case of digenic AS with novel digenic missense variants in COL4A4 (c.827G>C, p.Gly276Ala) and COL4A5 (c.4369G>C, p.Gly1457Arg).
UNASSIGNED: The patient was a 29-year-old Japanese man suffering from persistent microscopic hematuria and proteinuria without kidney function impairment. Kidney biopsy showed focal interstitial foam cell infiltration, global and segmental glomerulosclerosis. Immunofluorescence staining for collagen IV α5 was almost negative in the GBM and Bowman\'s capsule. Electron microscopy revealed irregular thickening with lamellation and segmental thinning of the GBM. Clinical and pathological findings were consistent with AS. Comprehensive next-generation sequencing revealed a heterozygous missense variant in COL4A4 (c.827G>C, p.Gly276Ala) in exon 1 and a hemizygous missense variant in COL4A5 (c.4369G>C, p.Gly1457Arg) in exon 49 on the patient\'s paternal and maternal alleles, respectively. The same digenic variants were detected in his sister, and she also showed a similar phenotype. After treatment with angiotensin-converting enzyme inhibitors, proteinuria decreased from 2.3 to 1.1 g/g creatinine, but occult blood persisted. During follow-up, kidney function has been preserved.
UNASSIGNED: The novel genotype of our case provides more information on the genotype-phenotype correlation of digenic XLAS, although long-term follow-up is required. The findings in the present case also indicate the importance of genetic tests for family members of a patient diagnosed with digenic AS.

Several neurological disorders, neurodevelopmental disorders, and neurodegenerative disorders have a genetic element with various clinical presentations ranging from mild to severe presentation. Neurological disorders are rare multifactorial disorders characterized by dysfunction and degeneration of synapses, neurons, and glial cells which are essential for movement, coordination, muscle strength, sensation, and cognition. The cerebellum might be involved at any time, either during development and maturation or later in life. Herein, we describe a spectrum of NDDs and NDs in seven patients from six Egyptian families. The core clinical and radiological features of our patients included dysmorphic features, neurodevelopmental delay or regression, gait abnormalities, skeletal deformities, visual impairment, seizures, and cerebellar atrophy. Previously unreported clinical phenotypic findings were recorded. Whole-exome sequencing (WES) was performed followed by an in silico analysis of the detected genetic variants\' effect on the protein structure. Three novel variants were identified in three genes MFSD8, AGTPBP1, and APTX, and other previously reported three variants have been detected in \"TPP1, AGTPBP1, and PCDHGC4\" genes. In this cohort, we described the detailed unique phenotypic characteristics given the identified genetic profile in patients with neurological \"neurodevelopmental disorders and neurodegenerative disorders\" disorders associated with cerebellar atrophy, hence expanding the mutational spectrum of such disorders.