Long-term follow-up and novel variant in Suleiman-El-Hattab syndrome: Expanding the genotypic and clinical spectrum of a rare neurodevelopmental disorder.

Suleiman-El-Hattab syndrome (SULEHS, OMIM #618950) is an autosomal recessive multisystem developmental disorder characterized by distinctive facial appearance, global developmental delay/intellectual disability, poor expressive speech and happy demeanor. SULEHS is an ultra-rare disorder associated with biallelic loss-of-function variants of the TASP1 gene, and up-to-date, seven patients from five families have been reported in the literature. Loss of TASP1 function has been reported to alter H3K4 histone modifications and expression of TFIIA and HOX transcription factors in the SULEHS phenotype. In this report, a new patient molecularly diagnosed with SULEHS by a novel homozygous c.404-2A > G variant in the TASP1 gene is presented with the long-term follow-up. Although the majority of the patient's clinical characteristics were similar to those of previously reported SULEHS patients, this study was the first to describe some additional anomalies, such as cystic hygroma, increased nuchal thickness, coarctation of the aorta, pulmonary stenosis, pulmonary sequestration anomaly, chronic constipation, encephalomalacia, and aggressive behavior. Because of the remarkable similarities between the clinical features of Baraitser-Winter syndrome (BRWS) and the patient, BRWS was considered the most likely diagnosis before the molecular diagnosis. Network analysis also supported that the interaction of the SULEHS-associated TASP1 gene with the BRWS-associated ACTB and ACTG1 genes through common intermediate molecules. Overall, despite the existence of differences in clinical features, inheritance patterns, and underlying pathophysiology between BRWS and SULEHS, both diseases could be considered in the differential diagnosis due to the high clinical similarities, including the dysmorphic features, growth parameters, neurodevelopmental phenotype, neurological problems, and multisystem involvement. Additionally, this report could contribute to a better understanding of the genotypic and clinical features of SULEHS by describing a novel pathogenic variant and new clinical features, such as prenatal manifestations.

Expanding the phenotype and genotype in Thauvin-Robinet-Faivre syndrome: A new patient with a novel variant and additional clinical findings.

Thauvin-Robinet-Faivre syndrome (TROFAS; OMIM #617107) is a rare autosomal recessive overgrowth syndrome characterized by generalized overgrowth, dysmorphic facial features, and delayed psychomotor development caused by biallelic pathogenic variants in the FGF-1 intracellular binding protein (FIBP) gene. To date, only four patients from two families have been reported. In this report, we present a 4-year-old male patient with generalized overgrowth and delayed developmental milestones consistent with this syndrome. In addition, he has unique features that were not reported in previous patients, including drooling, recurrent pulmonary infections, chronic pulmonary disease, hyperextensible elbow joints, hypoplastic nipples, unilateral cryptorchidism, and frequent spontaneous erections. We identified a homozygous, likely pathogenic variant, c.415_416insCAGTTTG (p.Asp139AlafsTer3), which causes a frameshift in the FIBP. Additionally, we identified a homozygous missense variant in the Toll-like receptor 5(TLR5) gene and a hemizygous missense variant in the chloride voltage-gated channel 4 (CLCN4) gene, with uncertain significance in either case. In this article, we set out the new observations and also discuss the frequency of the characteristic findings of the syndrome in the patients so far reported.

A homozygous missense variant in the WRN gene segregating in a family with progressive pulmonary failure with recurrent spontaneous pneumothorax and interstitial lung disease.

Interstitial lung disease (ILD) is a condition affecting the lung parenchyma by inflammation and fibrosis and can be caused by various exposures, connective tissue diseases (CTD), and genetic disorders. In this report, a family with five patients having progressive respiratory failure that begins with coughing in adolescence, followed by dyspnea and recurrent spontaneous pneumothorax, and death in early adulthood is presented. The patients were diagnosed to have ILD through clinical and radiological evaluations. Molecular genetic analyses of the family provided two homozygous rare variants in the WRN and SFXN5 genes, co-segregating with the phenotype. The network analyses pointed out that the variant in the WRN, rather than that in the SFXN5 gene, could be the main factor in the existence of the ILD phenotype, putatively through the altered DNA repair and telomere maintenance pathways. In silico analyses suggested that the variant could affect the exonuclease activity or the stability of the WRN protein. Moreover, the adolescent-onset pulmonary phenotype described in the case has not been reported in Werner Syndrome, the only disease known to be associated with biallelic WRN pathogenic variants. Thus, the present phenotype could be either a very atypical presentation of Werner syndrome or a new clinical entity associated with the WRN gene.

Aetiological Evaluation of Oligodontia in a Three-Generation Family.

PURPOSE: The aim of this study was to assess the genetic evaluation of a three-generation consanguineous family with isolated oligodontia. MATERIALS AND METHODS: A 16-year-old male patient who had been referred for orthodontic treatment due to the presence of oligodontia, and his family members who presented several missing teeth had been enrolled in the study. Clinical and radiological assessments and genetic analysis including whole-exome sequencing were performed. RESULTS: Genetic evaluations revealed both homozygous and heterozygous mutations (c.T682A:p.F228I) in the WNT10A gene of six affected members of the family. Higher frequency of agenesis of mandibular second molar was found in homozygous relative to heterozygous WNT10A mutations. CONCLUSION: The present findings have provided evidence for a known variant in the WNT10A gene in a three-generation consanguineous family with isolated oligodontia, while the results confirmed that cases with homozygous mutation revealed clinical heterogeneity.

Warburg Micro Syndrome 1 due to Segmental Paternal Uniparental Isodisomy of Chromosome 2 Detected by Whole-Exome Sequencing and Homozygosity Mapping.

Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by microcephaly, cortical dysplasia, intellectual disability, ocular abnormalities, spastic diplegia, and microgenitalia. WARBM has 4 subtypes arising from pathogenic variants in 4 genes (RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20). Here, we report on a patient with a homozygous pathogenic c.665delC (p.Pro222HisfsTer30) variant in the RAB3GAP1 gene identified by whole-exome sequencing (WES) analyses. Only his father was a heterozygous carrier, and homozygosity mapping analysis of the WES data revealed large loss-of-heterozygosity regions in both arms of chromosome 2, interpreted as uniparental isodisomy. This uniparental disomy pattern could be due to paternal meiosis I nondisjunction because of the preserved heterozygosity in the pericentromeric region. This report provides novel insights, including a rare form of UPD, usage of homozygosity mapping analysis for the evaluation of isodisomy, and the first reported case of WARBM1 as a result of uniparental isodisomy.

Identification of Three Novel FBN1 Mutations and Their Phenotypic Relationship of Marfan Syndrome.

BACKGROUND: Marfan syndrome (MS), a connective tissue disorder that affects ocular, skeletal, and cardiovascular systems, is caused by heterozygous pathogenic variants in FBN1. To date, over 1800 different pathogenic variants have been reported. METHODS: In the present study, FBN1 sequence analysis was performed in a family and two unrelated patients with MS. RESULTS: Three novel pathogenic variants were detected. Two of these variants [c.6610T>C; p.(Cys2204Arg) and c.1956T>G; p.(Cys652Trp)], which affect a cysteine residue, were associated with MS with ectopia lentis, whereas the mutation causing a premature stop codon [c.2506delA; p.(Ser836ValfsX10)] leads to a classical MS of a milder phenotype. CONCLUSION: We anticipate that the three novel pathogenic variants identified in this study will provide further support for the clinical relevance of variants in the large FBN1 gene.

Investigation of CYP2D6 Gene Polymorphisms in Turkish Population.

Pharmacogenetics is interested in the variable response to drugs depending on the genetic constitution of an individual. Depending on the genetic variation in individuals known as polymorphism; leads to differences in the types of proteins, enzymes or receptors that play a role in the elimination of drugs. Investigation of the correlation between the genotype with phenotype changes in drug metabolism is among the most important topics of today. CYP2D6 gene polymorphisms show clinical efficiency in the use of especially antidepressants, neuroleptics, antiarrhythmic, antihypertensive, beta blocker, and morphine derivatives. Poor metabolizers have been shown to demonstrate adverse drug reactions to these drugs. The plasma concentrations tend to increase inducing side effects after using a standard dose in poor metabolizers. The ratio of poor metabolizers in Caucasians is 5-10%, whereas 3.4-3.8% of the Turkish population. The allele frequencies of CYP2D6 *2, *3, *4 and *10 were found in 35%, 6%, 10% and 26% respectively in 200 healthy controls. The ratio of poor metabolizers in our population revealed as 1%. Genotyping of CYP2D6 is very important for determining a better genotype-phenotype relation.

Mutations affecting the BHLHA9 DNA-binding domain cause MSSD, mesoaxial synostotic syndactyly with phalangeal reduction, Malik-Percin type.

Mesoaxial synostotic syndactyly, Malik-Percin type (MSSD) (syndactyly type IX) is a rare autosomal-recessive nonsyndromic digit anomaly with only two affected families reported so far. We previously showed that the trait is genetically distinct from other syndactyly types, and through autozygosity mapping we had identified a locus on chromosome 17p13.3 for this unique limb malformation. Here, we extend the number of independent pedigrees from various geographic regions segregating MSSD to a total of six. We demonstrate that three neighboring missense mutations affecting the highly conserved DNA-binding region of the basic helix-loop-helix A9 transcription factor (BHLHA9) are associated with this phenotype. Recombinant BHLHA9 generated by transient gene expression is shown to be located in the cytoplasm and the cell nucleus. Transcription factors 3, 4, and 12, members of the E protein (class I) family of helix-loop-helix transcription factors, are highlighted in yeast two-hybrid analysis as potential dimerization partners for BHLHA9. In the presence of BHLHA9, the potential of these three proteins to activate expression of an E-box-regulated target gene is reduced considerably. BHLHA9 harboring one of the three substitutions detected in MSSD-affected individuals eliminates entirely the transcription activation by these class I bHLH proteins. We conclude that by dimerizing with other bHLH protein monomers, BHLHA9 could fine tune the expression of regulatory factors governing determination of central limb mesenchyme cells, a function made impossible by altering critical amino acids in the DNA binding domain. These findings identify BHLHA9 as an essential player in the regulatory network governing limb morphogenesis in humans.

Evaluation of GenoFlow Thrombophilia Array Test Kit in its detection of mutations in Factor V Leiden (G1691A), prothrombin G20210A, MTHFR C677T and A1298C in blood samples from 113 Turkish female patients.

Thrombophilia is a heritable blood disease characterized by an increased tendency to form abnormal blood clots that can block blood vessels. In obstetrics and gynecology, it has been shown by a number of reports that a proportion of recurrent miscarriages involve thrombophilia-related mutations, in particular, Factor V G1691A, prothrombin G20210A, and MTHFR C677T and A1298C. In this study, we examined the frequency of these four mutations in 113 female Turkish patients who had prior complications in pregnancy, using the DiagCor GenoFlow Thrombophilia Array Test kit. Heterozygous MTHFR C677T and A1298C mutations were detected in 46% of the patients, and among these patients, 60% of them carried double heterozygous mutations. In contrast, the heterozygous Factor V G1691A and prothrombin G20210A were detected only in a smaller number of patients, respectively, 13% and 3%. The GenoFlow kit demonstrated 100% concordance with results from Sanger sequencing, which can be translated into sensitivity and specificity both at 100% within this series of patients.

Chromosomal-array analysis reveals partial 11q duplication and partial 12p deletion in a mildly affected case.

Partial trisomy 11q is a rare syndrome and may be observed due to an intra-chromosomal duplication or an inter-chromosomal insertion. The deletions of the short arm of chromosome 12 are also uncommon structural aberrations. Only a small fraction of structural chromosome anomalies are related to the unbalanced progeny of balanced translocation carrier parents. We here report on a 10-month-old baby boy who shows a very mild phenotype related to unique chromosomal abnormality, partial trisomy of 11q, and partial monosomy of 12p, due to the maternal balanced reciprocal translocation (11;12). The proband showed a 49.64 Mb duplication of 11q14.1-q25 and 0.44 Mb deletion of 12p13.33 in chromosomal array analysis. Since it is known that the duplications may cause a milder phenotype than deletions. Dysmorphic facial features, minor cardiac anomalies, respiratory distress, central nervous system anomalies, and psychomotor delay observed in the patient was similar to the reported pure 11q duplication cases, while behavioral problems observed in pure monosomy 12p cases could not be evaluated due to the young age of the patient. Phenotype-genotype correlation will be discussed in view of all the reported pure partial 11q trisomies and pure partial 12p deletion cases.

Rectal duplications accompanying rectovestibular fistula: report of two cases.

Rectal duplication (RD) cysts are rare congenital anomalies that can be diagnosed with the presence of another opening in the perineum. They seldom accompany anorectal malformations (ARM). Two cases of RD accompanying ARM at opposite ends of the phenotypic spectrum, are described. A 3-month-old baby and a 2-year-old girl with ARM were scheduled for posterior sagittal anorectoplasty. The infant had an orifice at the anal dimple and the other had an orifice at the vestibulum posterior to the rectovestibular fistula. The infant presented with no other anomalies whereas the older one presented with an unusual coexistence of caudal duplication and caudal regression syndromes. Perioperatively both orifices were found to be related to retrorectal cysts, and were excised. Clinicians should always be alert when dealing with complex malformations. Because these malformations have variable anatomical and clinical presentations, they can represent a diagnostic and therapeutic challenge.

A Turkish family with Nance-Horan Syndrome due to a novel mutation.

Nance-Horan Syndrome (NHS) is a rare X-linked syndrome characterized by congenital cataract which leads to profound vision loss, characteristic dysmorphic features and specific dental anomalies. Microcornea, microphthalmia and mild or moderate mental retardation may accompany these features. Heterozygous females often manifest similarly but with less severe features than affected males. We describe two brothers who have the NHS phenotype and their carrier mother who had microcornea but not cataract. We identified a previously unreported frameshift mutation (c.558insA) in exon 1 of the NHS gene in these patients and their mother which is predicted to result in the incorporation of 11 aberrant amino acids prior to a stop codon (p.E186Efs11X). We also discussed genotype-phenotype correlation according to relevant literature.

Association of microsomal epoxide hydrolase gene polymorphism and pre-eclampsia in Turkish women.

AIM: To assess the association between human epoxide hydrolase exon 3 and 4 polymorphisms and pre-eclampsia by carrying out a case-control study in Turkish women. METHODS: DNA was extracted from peripheral blood leukocytes, and genotype distribution of exon 3 and exon 4 of epoxide hydrolase gene (EPHX) was carried out in 271 patients and 155 controls. RESULTS: There was no statistically significant difference in the distribution of genotypes between pre-eclampsia without HELLP and pre-eclampsia plus HELLP cases and controls for the exon 3 and 4 polymorphism of EPHX. However, we found a significant association between the predicted enzyme activity level and pre-eclampsia (P = 0.018). The distribution of subjects with predicted high, intermediate and low microsomal epoxide hydrolase enzyme (EPHX) activity were 23.2, 38.8 and 38% in cases and 12, 47.3 and 40.7% in controls, respectively. CONCLUSION: Although we could not find any association between genetic variability in exon 3 and 4 of EPHX and pre-eclampsia, genetic variability in these two exons jointly modifies the predicted enzyme activity and may be a risk factor for pre-eclampsia.

Lack of association between the CYP11B2 gene polymorphism and preeclampsia, eclampsia, and the HELLP syndrome in Turkish women.

OBJECTIVES: It is possible that altered control of aldosterone synthase gene (CYP11B2) expression or translation may be responsible for hypertension. Hypertension is one of the major components of preeclampsia. We present here a study investigating the association between the CYP11B2 gene polymorphism in the promoter region at the position of -344 and preeclampsia. STUDY DESIGN: We analyzed a group of Turkish women for preeclampsia (n=143), eclampsia (n=36), and the HELLP syndrome (n=55) and compared them with controls (n=147). Genotypes for CYP11B2 were determined by polymerase chain reaction followed by digestion with BsuRI restriction enzyme. RESULTS: The -344T/T, -344C/T, and -344C/C genotypes were found at comparable frequencies among the study groups, between the study and control groups, and between the study groups combined and the control group (p>0.05). We combined the genotypes of TC and CC (polymorphic) and compared them with the TT (wild-type) genotype. There was no significant difference in the frequency of the TC plus CC genotypes among the study groups, between the study and control groups, and between the study groups combined and the control group (p>0.05). There was no association of the CYP11B2 polymorphism among the preeclampsia, eclampsia, and HELLP groups and controls. CONCLUSIONS: The CYP11B2 gene polymorphism is not directly associated with preeclampsia, eclampsia, and the HELLP syndrome in women with these conditions. Therefore, this polymorphism may not be a risk factor for these disorders, at least not in the Turkish population.

No association of polymorphisms in the glutathione S-transferase genes with pre-eclampsia, eclampsia and HELLP syndrome in a Turkish population.

AIM: There is substantial evidence that genetic factors play a role in pre-eclampsia. The aim of this study was to determine whether genetic variability in the encoding of genes for glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) contributes to individual differences in susceptibility to pre-eclampsia, eclampsia, or hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). METHODS: A total of 221 women with pre-eclampsia, eclampsia and HELLP syndrome and 147 healthy female controls were genotyped for GSTM1 and GSTT1 polymorphisms by polymerase chain reaction (PCR). Statistical evaluation of differences in polymorphic rates was carried out using chi(2) analysis. RESULTS: This study included 140 pre-eclamptic, 33 eclamptic and 48 HELLP syndrome cases and 147 healthy controls. The frequencies for the GSTM1 null genotype were 58%, 45%, and 60% for pre-eclampsia, eclampsia, and HELLP syndrome, respectively, and in controls it was 55%. The distribution of the GSTT1 null genotype was 22%, 21%, and 27% for pre-eclampsia, eclampsia, and HELLP syndrome, respectively, and in controls it was 22%. There was no significant association between GSTM1 and GSTT1 polymorphisms and pre-eclampsia, eclampsia, and HELLP syndrome. CONCLUSION: Our data do not support a role for polymorphisms of the GSTM1 and GSTT1 genes in the pathogenesis of pre-eclampsia, eclampsia and HELLP syndrome.

Autosomal recessive mesoaxial synostotic syndactyly with phalangeal reduction maps to chromosome 17p13.3.

Previously we have described a novel and distinct form of non-syndromic osseous syndactyly segregating in an autosomal recessive pattern in a consanguineous Pakistani family. The limb findings include mesoaxial reduction of the fingers, synostoses of the third and fourth metacarpals with associated single phalanges, fifth finger clinodactyly, and preaxial webbing of toes. We identified another published report of this phenotype in a large, inbred Turkish family. In the present study we mapped the phenotype in the Pakistani and Turkish families to chromosome 17p13.3 (multipoint LOD score 5.1). The identification of a single locus for this complex limb malformation in two families with distinct ethnic backgrounds supports the hypothesis that this is a distinct form of syndactyly. Since this form of syndactyly is phenotypically distinct from the previously described eight types, we propose to name this phenotype mesoaxial synostotic syndactyly with phalangeal reduction (MSSD, type IX syndactyly, Malik-Percin type).