Esener Z, Yücesoy MA, Gezdirici A
… +11 more, Dogan M, Turkyilmaz A, Tekedereli I, Bas H, Tekmenuray-Unal A, Kocagil S, Citli S, Ozturk M, Ceylan EI, Karaman V, Aslanger AD
Hypohidrotic ectodermal dysplasias are a genetic condition affecting ectoderm-derived structures such as hair, teeth, nails, and sweat glands, resulting from variations in the EDA, EDAR, EDARADD, and WNT10A genes. This s...Hypohidrotic ectodermal dysplasias are a genetic condition affecting ectoderm-derived structures such as hair, teeth, nails, and sweat glands, resulting from variations in the EDA, EDAR, EDARADD, and WNT10A genes. This study examined 32 cases from 25 unrelated families from Türkiye, identifying seven novel variants in the EDA, EDAR, and WNT10A genes. The distribution of genetic alterations across the cohort revealed that 44% of the families (11/25) harbored variants in EDA, whereas EDAR and WNT10A variants were identified in 32% (8/25) and 24% (6/25) of families, respectively. Clinical evaluation revealed the characteristic hypohidrotic ectodermal dysplasia triad of hypotrichosis, hypodontia, and hypohidrosis was observed in 87.5% of cases, along with other symptoms such as dry skin, atopic dermatitis, and developmental delays. All cases presented with hair, eyebrow, and eyelash abnormalities, ranging in severity from subtle thinning to marked hypotrichosis. Among the cohort, one case exhibited severe atopic dermatitis as the predominant symptom. Targeted next-generation sequencing and clinical exome sequencing were employed to determine the genetic basis of the condition, emphasizing the importance of early diagnosis for targeted interventions. This study expands the genetic and phenotypic spectrum of hypohidrotic ectodermal dysplasia, presenting a comprehensive overview of molecular findings and genotype-phenotype correlations in the population from the Turkish population.
Over the past 15 years, molecular methods for human genome analysis have evolved significantly, becoming integral to routine genetic diagnostics. Among various genomic alterations, copy-number variations (CNVs) are parti...Over the past 15 years, molecular methods for human genome analysis have evolved significantly, becoming integral to routine genetic diagnostics. Among various genomic alterations, copy-number variations (CNVs) are particularly important as sources of both benign and pathogenic variants. Accurate assessment of these variants' clinical implications is critical, especially for rare, non-recurrent CNVs and for susceptibility loci linked to neurodevelopmental disorders (NDDs). To address these challenges, the French AchroPuce CNV Interpretation Working Group proposes a novel classification termed "PIEV," referring to CNVs associated with NDDs characterized by incomplete penetrance and variable expressivity. This category complements the existing five-tier ACMG classification system, supporting genetic professionals in harmonizing practice through standardized French national guidelines, thereby enhancing genetic counseling and clinical interpretation precision. Distinguishing clearly pathogenic variants from those with incomplete penetrance is crucial, and the consistent classification of these CNVs independently of the clinical context is essential. Clinical significance assessments should entail collaboration between biologists and multidisciplinary clinical teams, especially in prenatal diagnostics. The working group maintains an annually reviewed curated list of recurrent neurodevelopmental CNVs with reduced penetrance and provides consensus recommendations with a customized interpretation tool to enhance national consistency in CNVs reporting.
Humeroradial synostosis (HRS) is a rare congenital limb malformation, characterised by fusion of the humeral and radial bones, leading to functional disability of the elbow joint. HRS may be reported in familial or spora...Humeroradial synostosis (HRS) is a rare congenital limb malformation, characterised by fusion of the humeral and radial bones, leading to functional disability of the elbow joint. HRS may be reported in familial or sporadic cases and observed either isolated or as part of a syndromic condition. According to an extensive review of the literature, a dozen known conditions may comprise an HRS. The present review aims to propose an updated classification based on molecular pathways (chondrogenesis and osteogenesis; limb development and patterning; genome regulation), combined with a concise overview of the conditions associated with HRS. This knowledge could guide molecular analyses, patient management and genetic counselling. As some cases remain unexplained, further genetic and epidemiological studies are required to evaluate the contribution of genetic and environmental factors in HRS physiopathology.
Osteogenesis imperfecta (OI) is a heritable disorder characterized by bone fragility and marked genetic and phenotypic heterogeneity. This study explores the molecular and clinical spectrum of OI, with a focus on autosom...Osteogenesis imperfecta (OI) is a heritable disorder characterized by bone fragility and marked genetic and phenotypic heterogeneity. This study explores the molecular and clinical spectrum of OI, with a focus on autosomal recessive (AR) forms, therapeutic outcomes, and bone mineral density (BMD) in carriers of AR OI-associated gene variants from the Indian population. A total of 78 clinically suspected OI patients were analyzed, yielding a high diagnostic rate of 92.3%. Exome sequencing was performed in all cases, with whole-genome sequencing in selected exome-negative cases. Autosomal dominant (AD) and AR OI accounted for 66% and 34% of cases, respectively. P3H1 (n = 11) was the most frequently implicated AR gene causing OI, followed by SERPINF1 (n = 5) and WNT1 (n = 4), with 79% of AR variants being novel. Phenotypic evaluation (n = 67) revealed fractures, short stature (87%), and bony deformities (84%) as predominant features. A rare homozygous COL1A1 variant was identified in one patient, while another patient harbored additional variants in AD OI genes, suggesting a potential digenic or modifier effect. Phenotypic severity followed the order from most to least severe: AR genes > COL1A2 (substitution and non-substitution) > COL1A1 (substitution > non-substitution). A self-designed, preliminary clinical severity scoring system ranked CRTAP followed by P3H1, as the AR genes associated with the most severe phenotypes. Therapeutic assessment showed a significant reduction in fracture incidence following zoledronate therapy only in the COL1A1 group, with no notable improvements in the COL1A2 or AR groups. Additionally, BMD evaluation in carrier parents of AR gene causing OI indicated a higher predisposition to low BMD among WNT1 gene carriers. However, these findings are preliminary and limited by small sample size. This study provides an extensive genotypic and phenotypic characterization of OI in the Indian population, with a focus on AR OI. It documents differential therapeutic responses among genetic subgroups and provides preliminary observations on BMD in carrier parents of AR OI-an aspect that has been less explored previously and suggest the need for tailored management strategies. The findings in this study also raise the possibility of genetic modifiers contributing to phenotypic variability, warranting further investigation.
Alatawi A, Alshehri O, Alessa A
… +15 more, Al Mutairi F, AlSaleh N, Eyaid W, Alsamri A, Faqeih E, Mushiba A, Saleh M, Alotaibi M, Tabarki B, Aljadhai YI, Katsonis P, Lichtarge O, Alkuraya FS, Alfadhel M, Almannai M
SLC25A42 encodes a mitochondrial carrier that is responsible for the import of CoA into mitochondria. Biallelic pathogenic variants in SLC25A42 have been associated with a recently described mitochondrial disorder charac...SLC25A42 encodes a mitochondrial carrier that is responsible for the import of CoA into mitochondria. Biallelic pathogenic variants in SLC25A42 have been associated with a recently described mitochondrial disorder characterized by encephalomyopathy with variable severity. To date, 24 affected individuals from 16 different families have been reported. Most are of Arab descent who harbor the founder variant in SLC25A42 (c.871A>G, p.Asn291Asp). In this report, we present 23 additional individuals from 19 unrelated families and their clinical, radiological, and molecular findings. We show again that SLC25A42-related mitochondrial disorder is associated with extremely variable severity. Some individuals with mild presentation may be unrecognized, while others are prone to metabolic decompensations with neuro-regression and irreversible neurological insult, making early diagnosis important.
Autophagy is a critical cellular process for maintaining proteostasis and neuronal health. Disruption of this pathway is increasingly recognized in pediatric neurodegenerative disorders. Here, we study a novel previously...Autophagy is a critical cellular process for maintaining proteostasis and neuronal health. Disruption of this pathway is increasingly recognized in pediatric neurodegenerative disorders. Here, we study a novel previously uncharacterized homozygous and autosomal recessive missense variant, c.1372G>C (p.Gly433Ala), in the autophagy gene ATG2A, identified in a 3-year-old female proband presenting with developmental regression, seizures, cerebellar ataxia, and MRI-confirmed diffuse cerebral and cerebellar atrophy. The affected residue, Gly433, is evolutionarily conserved across eukaryotes and predicted to be structurally and functionally critical. Computational modeling and molecular dynamics simulations revealed that the G433A substitution induces local β-sheet extension, increased protein flexibility, higher aggregation propensity, and global structural destabilization. Proband-derived fibroblasts expressing ATG2A-G433A showed normal transcript and protein levels, but exhibited mislocalization of ATG2A to the cytosol, reduced colocalization with LC3B, loss of autophagosome formation, and a marked increase in protein aggregates. Proteotoxic stress was further evidenced by significant accumulation of Proteostat- and SQSTM1-positive granules. Additionally, transcript levels of unfolded protein response markers (GRP78, PERK, ATF4, and CHOP) were significantly upregulated, suggesting increased ER stress signaling. Cell cycle analysis revealed a substantial increase in cell death in proband fibroblasts. Overall, our findings identify ATG2A as a potentially novel disease gene and its G433A variant as a pathogenic substitution that disrupts autophagy and proteostasis, driving neurodegeneration via aggregation-prone misfolding and autophagy failure. This work depicts the first clinical spectrum of ATG2A-related neurodegenerative disorders and highlights the importance of autophagy maintenance in pediatric neurodevelopmental processes.
Cell-free DNA (cfDNA) screening for fetal aneuploidy is typically offered from 10 weeks of gestational age (GA) onward. Fetal fraction (FF) enrichment may enable screening before 10 weeks with a low failure rate. This st...Cell-free DNA (cfDNA) screening for fetal aneuploidy is typically offered from 10 weeks of gestational age (GA) onward. Fetal fraction (FF) enrichment may enable screening before 10 weeks with a low failure rate. This study aimed to assess the feasibility of cfDNA screening with in vitro enrichment before 10 weeks of gestation. 435 pregnant women were recruited between 7w0d and 9w6d of GA (EARLY samples) and scheduled for a second cfDNA sample after 11 weeks of GA (12w+ samples). 371 women provided both an EARLY and a 12w+ sample, and we compared cfDNA results between EARLY and 12w+ samples and sex at birth. For sex determination using cfDNA, EARLY, and 12w+ samples were 100% concordant with clinical sex at birth. In 170 male pregnancies, EARLY samples 5.9% had FF < 4% after enrichment. Seven aneuploidies were observed early, but eight at 12+ weeks (one false positive after invasive diagnostic testing). We observed 4.4% spontaneous abortions between the EARLY and 12w+ sampling. Our findings suggest that in vitro fetal enrichment provides sufficient cfDNA for reliable prenatal cfDNA screening results as early as 8 weeks, but one limitation lies in the high proportion of spontaneous abortions before 12w0d.
Loss-of-function variants in FREM1 have been demonstrated in Manitoba oculotrichoanal syndrome (MOTA) and bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome, but the broader phenotypic spectrum of FR...Loss-of-function variants in FREM1 have been demonstrated in Manitoba oculotrichoanal syndrome (MOTA) and bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome, but the broader phenotypic spectrum of FREM1 variants remains incompletely characterized. In this study, we report compound heterozygous variants in a prenatal case of bilateral renal agenesis. Exome sequencing revealed biallelic FREM1 variants: c.5622G>A (p.Trp1874*) and c.3274+4A>G (p.Gly1030_Ile1091del). Minigene and bioinformatic analyses confirmed that the splice site variant induces aberrant splicing and alters transcriptional expression levels. This finding underscores the crucial role of non-canonical splice site variants in FREM1 in the pathogenesis of bilateral renal agenesis.
Lodato V, Galli M, D'Angeli G
… +13 more, Bottillo I, Celli L, Turchetta R, Colizza A, Gianno F, Palmisano B, Stanganelli FRF, Bianco MR, Messineo D, Allegra E, Grammatico P, Riminucci M, Corsi A
Jones syndrome (JS) is an ultra-rare autosomal dominant condition characterized by gingival fibromatosis and progressive sensorineural hearing loss. It has been recently demonstrated in members of a Finnish family to co-...Jones syndrome (JS) is an ultra-rare autosomal dominant condition characterized by gingival fibromatosis and progressive sensorineural hearing loss. It has been recently demonstrated in members of a Finnish family to co-segregate with heterozygosity for a frameshift variant in the fifth and last exon of the repressor element 1-silencing transcription factor gene (REST). Here, we report the first Italian family in which JS was diagnosed in the proband, a 38-year-old woman, and in her mother. Exome Sequencing identified in both, but not in clinically unaffected members of the family (i.e., a sister and the brother of the proband), the heterozygous pathogenic variant c.2645T>G (p.Leu882*) in exon-5 of the REST gene. This study confirms that exon-5 REST variants cause JS.
DNA glycosylases play a crucial role in DNA repair mediated by the base excision repair (BER) pathway, and alterations in these enzymes have been associated with hereditary cancer predisposition. Recently, germline biall...DNA glycosylases play a crucial role in DNA repair mediated by the base excision repair (BER) pathway, and alterations in these enzymes have been associated with hereditary cancer predisposition. Recently, germline biallelic loss-of-function variants in MBD4 were shown to be responsible for a novel autosomal recessive multi-tumor predisposition syndrome, provisionally denominated as MBD4-associated neoplasia syndrome and characterized by the association of adenomatous polyposis, colorectal cancer, and acute myeloid leukemia (AML). Here, we studied the MBD4 gene in five individuals from four families affected by adenomatous polyposis and AML, who had been referred for genetic counselling at a single institution over a period of approximately 20 years. All patients with this phenotype presented homozygous deleterious germline variants in MBD4, of which one is a founder variant recurrent in three of the families, and another variant has not been previously described in the literature. Our work allowed a molecular diagnosis for these families and significantly contributes to expanding the knowledge about this emerging syndrome caused by MBD4 constitutional deficiency.
Bizot E, Jouni D, Rooryck C
… +11 more, Taylor J, Legendre M, Charbonnier L, Metreau J, Benaloun E, Pinson A, Quenum G, Bouligand J, Tachdjian G, Labrune P, Tosca L
To date, only one study describes three unrelated cases of neurodevelopmental disorders associated with duplications in 22q13.2, which include the TCF20 gene. In contrast, TCF20 variants and deletions are well characteri...To date, only one study describes three unrelated cases of neurodevelopmental disorders associated with duplications in 22q13.2, which include the TCF20 gene. In contrast, TCF20 variants and deletions are well characterized. Here, we report six new cases of 22q13.2 gain, including TCF20, identified through array-comparative genomic hybridization (array-CGH). Probands exhibited neurodevelopmental delay, and several presented with facial dysmorphism, abnormal growth parameters, and abnormalities affecting the skeletal, respiratory, genitourinary, and/or cardiovascular systems. We documented one 440 Kb triplication and five cases of duplication ranging from 82.5 Kb to 3.03 Mb in size. Co-segregation analysis of the CNV and clinical symptoms supports variable expressivity. However, the complete penetrance of these gains remains questionable compared to the known pathogenic variants and structural variations associated with loss of function. We discuss the genotype-phenotype correlations and hypotheses surrounding the impairment of TCF20 protein function.
Fassad MR, Valenzuela S, Oláhová M
… +18 more, Collier JJ, Knowles CVY, Mavraki E, Elbracht M, Güzel N, Herberhold T, Kurth I, Maier A, Mattern L, Saunders C, McCullagh H, Õunap K, Wortmann SB, Reis A, Zhang L, Gustafsson CM, McFarland R, Taylor RW
Mitochondrial diseases are a complex group of conditions exhibiting significant phenotypic and genetic heterogeneity. Genomic testing is increasingly used as the first step in the diagnostic pathway for mitochondrial dis...Mitochondrial diseases are a complex group of conditions exhibiting significant phenotypic and genetic heterogeneity. Genomic testing is increasingly used as the first step in the diagnostic pathway for mitochondrial diseases. We used next-generation sequencing followed by bioinformatic data analysis to identify potentially damaging variants in the POLRMT gene (NM_005035.4) in six new affected individuals. Structural protein analysis predicted the detrimental impact of variants on POLRMT protein structure. Patients show extended phenotypic abnormalities often presenting early in life with features including global developmental delay, cognitive impairment, short stature and muscular hypotonia. This study expands the genetic and phenotypic landscape of mitochondrial disease associated with POLRMT variants.
Minotti C, Terreri S, Del Fattore A
… +15 more, Lepri FR, Ruta R, Iascone M, Pezzoli L, Dentici ML, Novelli A, Armando M, Longo D, Novelli G, Barbuti D, Bartuli A, Cavallari U, Graziani L, Digilio MC, Sinibaldi L
TRRAP encodes a multidomain pseudokinase involved in histone acetyltransferase complexes. TRRAP pathogenic variants were linked to neurodevelopmental disorders, intellectual disability, congenital anomalies, and hearing...TRRAP encodes a multidomain pseudokinase involved in histone acetyltransferase complexes. TRRAP pathogenic variants were linked to neurodevelopmental disorders, intellectual disability, congenital anomalies, and hearing loss. We report on three unrelated patients with TRRAP missense variants. Patient #1, a girl with severe intellectual disability, autism features, and preaxial polydactyly, displays the c.5575C>T, p.(Arg1859Cys) variant. Patient #2, a boy with developmental delay and facial anomalies, harbors the c.5647G>A, p.(Gly1883Arg) variant. Patient #3, a girl with developmental delay, epilepsy, and renal artery stenosis, carries the c.8572C>T, p.(Arg2858Trp) variant. These new cases broaden the TRRAP phenotypic spectrum, updating genotype-phenotype correlations. Osteoclast differentiation in Patient #1 and TRRAP expression in osteoclasts and osteoblasts were analyzed, leading to the assumption of a role of TRRAP in bone remodeling and in the observed skeletal anomalies.
Marinakis NM, Kampouraki A, Veltra D
… +12 more, Tilemis FN, Vasilopoulou M, Dokou A, Georgiadou E, Karavergou E, Christolouka M, Alexopoulos A, Kirillidi D, Goudesidou M, Kosma K, Sofocleous C, Makrythanasis P
WDR91, a WD40 repeat domain-containing protein, is a key regulator of endosomal trafficking, lysosomal function, and autophagy. It acts as a Rab7 effector, forming a complex with WDR81 to modulate phosphatidylinositol 3-...WDR91, a WD40 repeat domain-containing protein, is a key regulator of endosomal trafficking, lysosomal function, and autophagy. It acts as a Rab7 effector, forming a complex with WDR81 to modulate phosphatidylinositol 3-kinase (PI3K) activity, endosomal maturation, and lysosome homeostasis. Loss-of-function variants in WDR91 are considered related to endosomal accumulation, impaired cargo degradation, and neurodegeneration. In this report, an autosomal recessive neurodevelopmental disorder is proposed, associated with WDR91 loss-of-function in a consanguineous family. The patient presented with severe microcephaly, dysmorphic features, and organomegaly, along with early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Whole-exome sequencing (WES) identified a homozygous splice site variant, NM_014149.4:c.1395+1G>A, predicted to disrupt the donor site and classified as likely pathogenic (PVS1, PM2). The variant was absent from population databases and our internal in-house cohort. Functional analysis supports a pathogenic role for the variant. WDR91 deficiency results in neuronal loss, cortical thinning, and impaired brain development, as evidenced in Wdr91 knockout models. Our study expands the clinical and genetic spectrum of WDR91-related disorders and highlights the need for further investigations to elucidate the precise molecular mechanisms underlying WDR91-associated pathogenesis.
We identified a PMS2 variant (NM_000535.7:c.2117del, p.Lys706Serfs*19) in 22 French-Canadian (FC) families from Quebec with Lynch syndrome (LS; n = 21) or constitutional mismatch repair deficiency (CMMRD; n = 1). We aime...We identified a PMS2 variant (NM_000535.7:c.2117del, p.Lys706Serfs*19) in 22 French-Canadian (FC) families from Quebec with Lynch syndrome (LS; n = 21) or constitutional mismatch repair deficiency (CMMRD; n = 1). We aimed to (a) confirm its founder origin, (b) assess its allele frequency in the FC population, and (c) determine its contribution to the risk of developing various cancers in this population. We identified a haplotype common to all c.2117del alleles spanning 666 kb to 1.37 Mb, confirming the founder nature of the variant. In affected cases, the variant was found in 0 out of 821 breast cancer cases, 8 out of 693 (1.15%) endometrial cancer (EC) cases, and 1 out of 191 (0.52%) colorectal cancer (CRC) cases. In unaffected persons, the variant was identified in 22/6347 newborns (0.35%) and in 21/18129 FC CARTaGENE cohort participants (0.12%). Within this cohort, an excess of CRC (odds ratio: 10.7; 95% CI: 1.42-80.1; p value = 0.022), but not EC, was seen among heterozygotes for the PMS2 founder variant. Analysis of the variant in 24 subregions of Quebec showed over-representation in 5 of them. Here, we report the most frequent genetic cause of mismatch repair deficiency syndromes identified thus far in the FC population of Quebec.
Cuillerier A, Goodman A, Lawrence C
… +15 more, Villeneuve-Cloutier N, Armour CM, Bhola PT, Bourque DK, Carter MT, Lazier J, Sawyer SL, Saleh M, Prasad C, Siu VM, Care4Rare Canada Consortium, Boycott KM, Hartley T, Dyment DA, Balci TB
Epilepsy is a relatively common condition with genetic factors contributing significantly to its etiology. Advances in next-generation sequencing have dramatically increased the number of known epilepsy genes, improving...Epilepsy is a relatively common condition with genetic factors contributing significantly to its etiology. Advances in next-generation sequencing have dramatically increased the number of known epilepsy genes, improving diagnostic capabilities and patient care. However, 50%-80% of epilepsy patients remain undiagnosed after genomic testing, which includes chromosomal microarray, multigene panels, and genome-wide sequencing. Reanalysis of existing exome sequencing data has shown promise in increasing diagnostic yield. In this study, we reanalyzed exome sequencing data from 87 individuals with unsolved epilepsy and developmental delay or intellectual disability in Ontario, Canada. Our approach combined clinical and translational research methodologies to identify genetic variants linked to epilepsy. We obtained a diagnostic yield of 14.9%, solving 13 participants, with 11 involving known genes and two novel gene discoveries. In addition, 11 potential diagnoses were identified, suggesting that further investigation could confirm additional diagnoses. Factors such as the inclusion of additional family data, new disease-gene associations, and technological advancements contributed to these findings. This study highlights the importance of reanalysis as a cost-effective and timely approach to improving diagnostic yield in epilepsy associated with neurodevelopmental delay.
PIK3C2A is a member of the class II phosphatidylinositol-3-kinases (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and of PI(4)P into PI(3,4)P2. These second messenger lipids reg...PIK3C2A is a member of the class II phosphatidylinositol-3-kinases (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and of PI(4)P into PI(3,4)P2. These second messenger lipids regulate a wide range of downstream signaling pathways involved in many physiological functions and cellular processes, including cell proliferation, growth, survival, motility, and metabolism. PIK3C2A is also involved in the regulation of primary cilia formation and maintenance and in the regulation of receptor-mediated endocytosis at the base of the cilium. PIK3C2A was recently related to a novel oculoskeletodental syndrome (OCSKD MIM#618440), combining short stature, coarse facial features, ocular, and skeletal abnormalities. We describe here the fifth family presenting a PIK3C2A-related syndrome characterized by pulverulent cataracts and deafness. Using trio exome sequencing, we identified two novel compound heterozygous variants in PIK3C2A for which functional testing was necessary to assess the effect of one of the variants. Cellular studies of patient's-derived skin fibroblasts revealed a normal PIK3C2A protein level but a defective enzyme. Ciliary and cellular phenotype studies showed in the patient's cells impaired cilia formation and function as well as a reduced proliferative capacity. This study expands the clinical and mutational spectrum of PIK3C2A-related syndrome.
Single nucleotide variants (SNVs) and copy-number variant (CNV) deletions involving TBX4 have been associated with pulmonary arterial hypertension, ischiocoxopodopatellar syndrome, and lethal lung developmental disorders...Single nucleotide variants (SNVs) and copy-number variant (CNV) deletions involving TBX4 have been associated with pulmonary arterial hypertension, ischiocoxopodopatellar syndrome, and lethal lung developmental disorders (LLDDs). Thus far, all large CNV deletions encompassing entire TBX4 have been found to have arisen de novo. Here, we present a three-generation family with three neonate siblings who died within 35-66 days due to histopathologically diagnosed LLDD. Whole-genome sequencing identified an ~108-kb CNV deletion encompassing TBX4 in all three infants. The deletion was also found in their mother with a history of pneumonia and persistent thick upper airway secretions and in the maternal grandfather who had surgically corrected genu valgum. RT-qPCR from the proband's lung biopsy showed a decrease of TBX4 transcript level greater than 50%, suggesting additional deregulation of TBX4 expression. Computational analyses of the TBX4 super-enhancer identified 15 candidate noncoding hypomorphic SNVs transmitted to the children exclusively from their father and absent in their mother and maternal grandfather. We show that SNV rs35827636T > C, previously proposed as potentially hypomorphic in an unrelated AcDys patient, reduced transcriptional activity of the TBX4 promoter in an episomal reporter assay. Moreover, Hi-C analysis predicted inter-TAD interaction between the TBX4 super-enhancer and its promoter-proximal region. Our data further demonstrate complex compound inheritance of LLDDs and resulting challenges for genetic counseling.
Progressive familial intrahepatic cholestasis (PFIC) syndromes are rare autosomal recessive disorders. We present the first detailed phenotype-genotype of PFIC children with normal gamma-glutamyltransferase (GGT) [normal...Progressive familial intrahepatic cholestasis (PFIC) syndromes are rare autosomal recessive disorders. We present the first detailed phenotype-genotype of PFIC children with normal gamma-glutamyltransferase (GGT) [normal GGT/PFIC] in an African population. Thirty-one pediatric patients belonging to 28 unrelated Egyptian families with normal GGT/PFIC were reported. Clinical, biochemical, histopathological, and genetic data were systematically analyzed. Patients were 15 males/16 females (55 ± 52 months at diagnosis). Apart from cholestasis, clinical features included severe pruritus (visual analogue scale 7.5 ± 3.4), hepatomegaly (80.6%), sleep deprivation (41.9%), and splenomegaly (19.4%). 13/28 families had ABCB11 variants (PFIC2), 6/28 families had ATP8B1 (PFIC1) and TJP2 (PFIC4) variants each, 2/28 had MYO5B variants (PFIC10), and one family had USP53 variants (PFIC7). Twenty-five disease-causing variants were reported, including 16 novel variants. PFIC1 patients were more severely affected compared to other PFIC syndromes, as the incidence of growth retardation, sibling deaths, skin changes, and progression to biliary diversion were all significantly higher (p value 0.006, 0.012, 0.037, and 0.012, respectively). In contrast, none of the 13 PFIC2 children progressed to biliary diversion, and all four PFIC10 children had normal liver transaminases. Our study expands the global phenotypic and genotypic knowledge of normal GGT/PFIC and will facilitate better care for the syndrome in Egypt.
We report a patient homozygous for the UROD c.185C>T (p.P62L) variant who presents with clinical features resembling familial porphyria cutanea tarda (PCT). This case highlights the limitations of rigid UROD-related porp...We report a patient homozygous for the UROD c.185C>T (p.P62L) variant who presents with clinical features resembling familial porphyria cutanea tarda (PCT). This case highlights the limitations of rigid UROD-related porphyria classifications and supports the existence of a phenotypic continuum modulated by genetic, epigenetic, and environmental factors.