Filippi syndrome: Three new families suggest that urinary system abnormalities may belong to clinical spectrum of the disease.

Filippi syndrome is a rare genetic disorder characterized by growth and neurodevelopmental delays, dysmorphism, and selective limb abnormalities. Although the syndrome was described approximately four decades ago, only a few families with molecularly confirmed diagnoses have been reported. In this article, we present three new patients of Filippi syndrome with unusual clinical and genetic aspects. These patients exhibited novel clinical features that have not previously been associated with Filippi syndrome, including renal hypoplasia/aplasia, renal cysts, renal cortical thinning, hypomelanotic, and hypermelanotic macules. All three patients had homozygous frameshift variants of the CKAP2L gene, specifically NM_152515.3: c.554_555del, c.981_982del, and c.1463_1467del, with the second being a novel variant. Given the limited number of reported Filippi syndrome patients to date and the ongoing discovery of new clinical aspects of the disease, exploring its potential connection with kidney and skin pigmentation abnormalities could be valuable for future research.

Two novel variants in SCARF2 gene underlie van den Ende-Gupta syndrome.

Van den Ende-Gupta syndrome (VDEGS) (MIM#600920) is characterized by skeletal and craniofacial abnormalities that include prominent ears, downslanting palpebral fissures, blepharophimosis, hypoplastic maxilla with or without a cleft palate, a narrow and convex nasal bridge and an everted lower lip, camptodactyly and arachnodactyly. Intelligence is normal. Recent studies have reported that patients with VDEGS have pathogenic variants in the SCARF2 gene on chromosome 22q11.21. Here, we report two Turkish patients with two novel variants [c.2291_2292insC (p.Ser765LeufsTer6) and c.488G>A (p.Cys63Tyr)] in the SCARF2 gene. In silico analysis predicted that both of these novel variants were pathogenic. To the best of our knowledge, this is the first case report of this syndrome in Turkey.

Early onset disease, anarthria, areflexia, and dystonia can be the distinctive features of SPG64, a very rare form of hereditary spastic paraplegias.

Hereditary spastic paraplegias (HSP) are a group of inherited, neurodegenerative disorders characterized by progressive gait impairment, lower extremity spasticity and increased patellar reflexes. More than 80 types of HSP have been defined to date. In complicated forms, lower limb spasticity and gait impairment is accompanied by an additional neurological finding. Autosomal recessive (AR) HSPs are usually identified in complicated forms and occur more frequently in countries where consanguineous marriage is more widespread. Next generation sequencing techniques, developed in the last decade, have led to the identification of many new types of HSP and reduced the "diagnostic odyssey." Whole exome sequencing (WES) can diagnose up to 75% of undiagnosed HSP patients. Targeted genetic analysis with good clinical phenotyping gives the best diagnostic yields for rare diseases. Clinical heterogeneity is prominent in AR complicated HSP. However, some clinical features complicating the disease or magnetic resonance imaging findings, including thin corpus callosum or white matter abnormalities, can help to distinguish some types. AR spastic paraplegia type 64 (SPG64) is a very rare HSP, caused by a mutation in the ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) gene, first described in 2014. To date only nine patients from five families have been reported. We present two siblings with a novel pathogenic variant in ENTPD1, diagnosed by WES, as the sixth published family. We propose that early onset in childhood, cognitive impairment, dysarthria/anarthria, dystonia and areflexia may be the distinctive features of SPG64 and more clinical evidence from families with pathogenic ENTPD1 variants is warranted.

From cataract to syndrome diagnosis: Revaluation of Warburg-Micro syndrome Type 1 patients.

Warburg-Micro syndrome (WARBM) is a rare autosomal recessively inherited neuro-ophthalmologic syndrome. Although WARBM shows genetic heterogeneity, the pathogenic variants in RAB3GAP1 were the most common cause of WARBM. In this study, we aimed to evaluate the detailed clinical and dysmorphic features of seven WARBM1 patients and overview the variant spectrum of RAB3GAP1 in comparison with the literature who were referred due to congenital cataracts. A previously reported homozygous variant (c.2187_2188delGAinsCT) was identified in three of these patients, while the other four had three novel variants (c.251_258delAGAA, c.2606+1G>A, and c.2861_2862dupGC). Congenital cataract and corpus callosum hypo/agenesia are pathognomonic for WARBM, which could be distinguished from other similar syndromes with additional typical dysmorphic facial features. Although there is no known phenotype and genotype correlation in any type of WARBM, RAB3GAP1 gene analysis should be previously requested as the first step of genetic diagnosis in clinically suspicious patients when it is not possible to request a multi-gene panel.

Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome.

Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu261 , Leu262 , and Arg265 in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling. Structural data predicted a gain-of-function role of substitutions at residues Leu262 and Arg265 exerted by disruption of the N-SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu261 , with possible impact on SHP2's catalytic activity/selectivity and proper interaction of the PTP domain with the regulatory SH2 domains. Consistent with that, biochemical data indicated that substitutions at codons 262 and 265 increased the catalytic activity of the phosphatase, while those affecting codon 261 were only moderately activating but impacted substrate specificity. Remarkably, these mutations underlie a relatively mild form of NS characterized by low prevalence of cardiac defects, short stature, and cognitive and behavioral issues, as well as less evident typical facial features.

Novel mutation in SUCLA2 identified on sequencing analysis.

Succinate-CoA ligase, ADP-forming, beta subunit (SUCLA2)-related mitochondrial DNA depletion syndrome is caused by mutations affecting the ADP-using isoform of the beta subunit in succinyl-CoA synthase, which is involved in the Krebs cycle. The SUCLA2 protein is found mostly in heart, skeletal muscle, and brain tissues. SUCLA2 mutations result in a mitochondrial disorder that manifests as deafness, lesions in the basal ganglia, and encephalomyopathy accompanied by dystonia. Such mutations are generally associated with mildly increased plasma methylmalonic acid, increased plasma lactate, elevated plasma carnitine esters, and the presence of methylmalonic acid in urine. In this case report, we describe a new mutation in a patient with a succinyl-CoA synthase deficiency caused by an SUCLA2 defect.

Familial cardiofaciocutaneous syndrome in a father and a son with a novel MEK2 mutation.

Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder belonging to the group of RASopathies. It is typically characterized by congenital heart defects, short stature, dysmorphic craniofacial features, intellectual disability, failure to thrive, and ectodermal abnormalities such as hyperkeratosis and sparse, brittle, curly hair. CFC syndrome is caused by dominant mutations in one of the four genes BRAF, MEK1, MEK2, and KRAS. Only three familial cases of CFC syndrome have been reported to date, whereas the vast majorities are sporadic cases due to de novo mutations. We report on a fourth familial case with transmission of CFC syndrome from father to son due to a novel heterozygous sequence change c.376A>G (p.N126D) in exon 3 of MEK2 gene. This observation further documents the possibility of vertical transmission of CFC syndrome, which appears to be associated with rare mutations and relatively mild intellectual disability in affected individual. The hypomorphic effect of specific mutations particularly regarding neurocognitive issues may be related to the variable fertility of affected individuals.

Gorlin-Chaudhry-Moss syndrome revisited: expanding the phenotype.

Gorlin-Chaudhry-Moss syndrome (OMIM 233500) is a rare congenital malformation syndrome with the cardinal manifestations of craniofacial dysostosis, hypertrichosis, underdeveloped genitalia, ocular, and dental anomalies. Since 1960, only six affected individuals have been reported. We report a 4-year and 6-month-old female patient with this phenotype and review the clinical presentation of all patients known so far. Previously unreported malformations of the extremities, larynx, and nose are also described, expanding the phenotype of this rare syndrome. Array-CGH analysis did not show pathological deletions or duplications.

A new nonsense mutation in the NF1 gene with neurofibromatosis-Noonan syndrome phenotype.

PURPOSE: Neurofibromatosis-Noonan syndrome is a rare autosomal dominant disorder which combines neurofibromatosis type 1 (NF1) features with Noonan syndrome. NF1 gene mutations are reported in the majority of these patients. METHOD: Sequence analysis of the established genes for Noonan syndrome revealed no mutation; a heterozygous NF1 point mutation c.7549C>T in exon 51, creating a premature stop codon (p.R2517X), had been demonstrated. RESULT: Neurofibromatosis-Noonan syndrome recently has been considered a subtype of NF1 and caused by different NF1 mutations. CONCLUSION: We report the case of a 14-year-old boy with neurofibromatosis type 1 with Noonan-like features, who complained of headache with triventricular hydrocephaly and a heterozygous NF1 point mutation c.7549C>T in exon 51.

Neurodevelopmental disorder with microcephaly, ataxia, and seizures syndrome: expansion of the clinical spectrum.

Neurodevelopmental disorder with microcephaly, ataxia, and seizures (NEDMAS) syndrome is a rare neurodevelopmental disorder characterized by moderate intellectual disability (ID), thin body habitus, microcephaly, seizures, ataxia, muscle weakness, and speech impairment. So far, only two families with NEDMAS have been reported. We report the clinical and molecular characteristics of three unrelated Turkish families with four NEDMAS patients. Whole-exome sequencing was used to search for the disease-causing variant. The main manifestations of the probands are severe developmental delay and ID, thin body habitus, and severe hypotonia. Brain imaging revealed bilateral cerebral and cerebellar diffuse atrophy. Sequencing results showed that both patients carried a novel missense variant c.1196C>T (p.Thr399Met) in the seryl-tRNA synthetase gene. Our findings help expand the variant spectrum of NEDMAS and provide additional information for diagnosing cases with atypical features.

Targeted next-generation sequencing (NGS) analysis of mutations in nonsyndromic tooth agenesis candidate genes : Analysis of a Turkish cohort.

PURPOSE: The goal of this study was to assess genes known to be associated with tooth agenesis with next-generation sequencing (NGS) and analyze the relationship between these mutations and tooth agenesis phenotypes. METHODS: The study included 49 individuals aged between 6 and 13 years. A total of 14 genes related to nonsyndromic tooth agenesis were selected for targeted NGS. Mutations in Msh homeobox 1 (MSX1), Wnt family member 10A (WNT10A), axis inhibition protein 2 (AXIN2), keratin 17 (KRT17), lipoprotein receptor 6 (LRP6), and secreted protein, acidic and rich in cysteine (SPARC)-related modular calcium-binding protein 2 (SMOC2) genes were investigated. RESULTS: Mutations in six genes were detected in 12 of 49 subjects. Fifteen variants were identified, including the unknown variants c.657G > C in MSX1, c.2029C > T in AXIN2, and c.1603A > T in LRP6. Second premolar tooth agenesis was observed in 43.3% of all tooth agenesis cases with mutations, and it was the predominant phenotype observed for each mutated gene, followed by tooth agenesis of the lateral incisors (20%). CONCLUSIONS: Variations in MSX1, WNT10A, AXIN2, KRT17, LRP6, and SMOC2 may be a risk factor for hypodontia or oligodontia in the Turkish population.

A case with oto-spondylo-mega-epiphyseal-dysplasia (OSMED): the clinical recognition and differential diagnosis.

The oto-spondylo-mega-epiphyseal-dysplasia (OSMED) phenotype is an autosomal recessive trait that is a skeletal dysplasia with the hallmark findings of limb shortening, multiple skeletal and radiological abnormalities, mid-face hypoplasia with a flat nasal bridge, small upturned nasal tip, and sensorineural hearing loss. A 3.5-year-old girl born to consanguineous Turkish parents had characteristic facial features at birth: mid-face hypoplasia, mild hypertelorism, upslanting palpebral fissures, prominent supraorbital ridges, depressed nasal bridge, small upturned nasal tip, long philtrum, and micrognathia. Radiological examination at three years of age revealed large flaring metaphyses and wide flat epiphyses. The humerus and femur showed the characteristic dumbbell shape. She had bilateral hearing loss with no ophthalmologic findings. There is continuing debate over the clinical overlap and differential diagnosis of OSMED syndrome. The patient was examined considering Weissenbacher-Zweymuller, Stickler type 3, Marshall syndrome, and Kniest dysplasia as possible differential diagnoses. We believe that the presented patient clinically manifested features of OSMED syndrome. We would like to point out that the management of OSMED calls for a coordinated multidisciplinary approach.

Fibrillin-1 gene intron 56 polymorphism in Turkish children with mitral valve prolapse.

OBJECTIVE: Mitral valvar prolapse is the most common anomaly of the mitral valve apparatus throughout childhood. Fibrillin is one of the structural components of the elastin-associated microfibrils found in the mitral valve. A case-controlled study has performed to investigate the relationship between fibrillin 1 gene intron 56 polymorphism and risk of mitral valvar prolapse in Turkish children. PATIENTS AND METHODS: A total of 77 patients with mitral valvar prolapse diagnosed by clinical evaluation and echocardiography and 89 normal children of same age and sex were studied. The fibrillin-1 gene intron 56 polymorphism was identified by the polymerase chain reaction-based restriction analysis. RESULTS: There was a significant difference in the distribution of fibrillin-1 gene intron 56 genotypes (p = 0.0001) and allelic frequency (p = 0.0001) between the cases and the controls. CONCLUSIONS: Patients with mitral valvar prolapse have higher frequencies of fibrillin-1 gene intron 56 GC genotypes. Healthy children have higher frequencies of fibrillin-1 gene intron 56 CC genotypes. We speculate that the higher frequency of fibrillin-1 gene intron 56 G-allele increases the risk of mitral valvar prolapse.

Two cases of Nicolaides-Baraitser syndrome, one with a novel SMARCA2 variant.

Nicolaides-Baraitser syndrome (NCBRS) (OMIM 601358) is an uncommon but well-recognized autosomal dominant entity that is characterized by sparse scalp hair, characteristic coarse facies, microcephaly, seizures, developmental delay, intellectual disability (ID) and prominence of the interphalangeal joints and distal phalanges. Seizures are also common finding besides developmental delay and ID, which is severe approximately in half, moderate in one third and mild in the remainder. Here, we report two Turkish patients with NCBRS. One has a novel variant [NM_003070.5:c.3389G>T p.(Gly1130Val)] and a mild-moderate phenotype, and the other has a known variant [NM_003070.5:c.2554G>A p.(Glu852Lys)] correlated with severe phenotype.

Implantation of cardiac defibrillator in an infant with hypertrophic cardiomyopathy and newly identified MYBP3 mutation.

Hypertrophic cardiomyopathy has the highest incidence rate among genetically inherited cardiac diseases. It develops as a result of mutations in genes in related to the sarcomere protein in cardiac muscle. Generally, this results in asymmetrical hypertrophy. Patients who are symptomatic and have a significantly narrow left ventricular undergo should receive surgical treatment, whereas patients with a sudden cardiac death risk should receive treatment with an implantable cardiac defibrillator. This paper presents an infant with hypertrophic cardiomyopathy who was recently identified as having a mutation that resulted in a deletion-insertion type framework shift in the gene MYBPC3, who had family history of sudden death at a young age, and received myectomy and treatment with an implantable cardiac defibrillator in the same session due to a severely narrowed left ventricular outflow tract.

Vocal cord immobility as a cause of aphonia in a child with 3p13p12 deletion syndrome encompassing FOXP1 gene.

Congenital bilateral laryngeal paralysis/immobilization is an uncommon condition and has been described as isolated or accompanying to some recognizable syndromes. Heterozygous mutations in the FOXP1 gene (605515) are related with intellectual disability and, language impairment with or without autistic features. Expressive language is more affected than receptive language and more than half of the patients experience oromotor dysfunction and/or feeding difficulties. Here we report a child with severe developmental, speech delay and aphonia which was considered due to bilaterally abductor vocal cord immobility. Interstitial 8700 kbp deletion encompassing FOXP1 gene was detected on 3p13p12 chromosomal region. Although it is known that FOXP1 defects are related to abnormalities in vocal communication, FOXP1-associated laryngomalacia or vocal cord paralysis/immobilization cases have not been reported yet. The FOXP1 defects are considered to be a cause of delay in speech, and it is suggested that vocal cord evaluation should be conducted in suspicious cases.

Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes.

The SPECC1L protein plays a role in adherens junctions involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. It modulates PI3K-AKT signaling and controls cranial neural crest cell delamination during facial morphogenesis. SPECC1L causative variants were first identified in individuals with oblique facial clefts. Recently, causative variants in SPECC1L were reported in a pedigree reported in 1988 as atypical Opitz GBBB syndrome. Six families with SPECC1L variants have been reported thus far. We report here eight further pedigrees with SPECC1L variants, including a three-generation family, and a further individual of a previously published family. We discuss the nosology of Teebi and GBBB, and the syndromes related to SPECC1L variants. Although the phenotype of individuals with SPECC1L mutations shows overlap with Opitz syndrome in its craniofacial anomalies, the canonical laryngeal malformations and male genital anomalies are not observed. Instead, individuals with SPECCL1 variants have branchial fistulae, omphalocele, diaphragmatic hernias, and uterus didelphis. We also point to the clinical overlap of SPECC1L syndrome with mild Baraitser-Winter craniofrontofacial syndrome: they share similar dysmorphic features (wide, short nose with a large tip, cleft lip and palate, blepharoptosis, retrognathia, and craniosynostosis), although intellectual disability, neuronal migration defect, and muscular problems remain largely specific to Baraitser-Winter syndrome. In conclusion, we suggest that patients with pathogenic variants in SPECC1L should not be described as "dominant (or type 2) Opitz GBBB syndrome", and instead should be referred to as "SPECC1L syndrome" as both disorders show distinctive, non overlapping developmental anomalies beyond facial communalities.

Y chromosome azoospermia factor region microdeletions and recurrent pregnancy loss.

OBJECTIVE: This study was undertaken to determine the prevalence of Y-chromosome microdeletions in couples with recurrent pregnancy loss (RPL) as compared with fertile couples. STUDY DESIGN: Forty-three men from couples with recurrent pregnancy loss, and 43 men from couples with a live birth and no history of miscarriages were recruited from Zekai Tahir Burak Woman Health, Education and Research Hospital. The DNA was tested for the presence of 4 sequence tagged sites (STSs) spanning 4 AZF regions: DYS220 (AZFb), DYS235, DYS236, and DYS237 (AZFd). RESULTS: Seven (7) of the 43 men (16%) from couples with recurrent pregnancy loss had microdeletions in 1 or more of the 4 segments studied, whereas none of the fertile men had any microdeletions (P < .05). Their microdeletions were all found specifically at locus DYS 220 (AZFb). CONCLUSION: The prevalence of the Y chromosome microdeletion in AZF region was much higher in men from couples with recurrent pregnancy loss than men in fertile couples. This study showed that Y chromosome microdeletion in AZF region may be a possible etiologic factor of recurrent pregnancy loss.