Molecular Syndromology[JOURNAL]
Sun
200 papers
A New Case with Weaver Syndrome: Delineating Natural Course and Growth Pattern, Further Clarifying Clinical Phenotype.
Ünsal Y, Yıldırım N, Buluş AD … +1 more , Kılıç E
Mol Syndromol · 2025 Apr · PMID 40176837 · Full text
INTRODUCTION: Weaver syndrome, rare syndromic cause of tall stature, presents with overgrowth, accelerated skeletal maturation, dysmorphic features, and camptodactly. Despite expanding knowledge and widespread use of gen...
INTRODUCTION: Weaver syndrome, rare syndromic cause of tall stature, presents with overgrowth, accelerated skeletal maturation, dysmorphic features, and camptodactly. Despite expanding knowledge and widespread use of genetic tests, differential diagnosis of tall statue may be challenging, complicating follow-up. Here we describe a patient with a variant in , underlining presenting features and natural course. CASE PRESENTATION: Twenty-month-old girl consulted for tall stature was born at term (birthweight: 2,600 g [-0.8 SDS], birth length: 54 cm [2.4 SDS]) as the third child of non-consanguineous parents. Without any other complaints, she was 15.2 kg (2.5 SDS) and her height was 95 cm (3.1 SDS). She was proportionately tall compared to her parents (target height: 156 cm [-1.1 SDS]). Endocrine evaluation did not reveal pathology, growth traced parallel to 97th percentile of growth curve. Karyotype analysis and fibrillin gene analysis were normal. As she had mild intellectual disability and minor dysmorphic features (broad forehead, mild hypertelorism, long philtrum, thin upper lip and a prominent chin dimple, bilateral camptodactyly), whole exome analysis including copy number variant changes that revealed a heterozygous variant on was performed when she was 14 years old. Weaver syndrome was diagnosed. CONCLUSION: Tall stature, height SDS exceeding target height SDS, tall stature at birth, normal growth rate, minor dysmorphic features, and mild intellectual disability should prompt syndromic etiology of tall stature. Further genetic analysis should be implemented. Diagnosis of rare syndromes is crucial for defining prognosis, organ involvement, and natural course, avoiding unnecessary endocrine investigations.
Discovery of a Novel Variant: Unveiling Epilepsy and Newly Associated Dysmorphic Traits in a Turkish Patient.
Colak Y, Yilmaz M, Kart PO … +3 more , Terali K, Turkyilmaz A, Cansu A
Mol Syndromol · 2025 Apr · PMID 40176836 · Full text
INTRODUCTION: Cullin-3, encoded by the , is a core component of the ubiquitin E3 ligase complex. Through binding to specific adapters, this scaffold protein mediates the ubiquitination of a number of substrates, targetin...
INTRODUCTION: Cullin-3, encoded by the , is a core component of the ubiquitin E3 ligase complex. Through binding to specific adapters, this scaffold protein mediates the ubiquitination of a number of substrates, targeting their proteasomal degradation. Pathogenic variations of the are thought to cause autism and neurodevelopmental disorders, but so far, few studies have been associated with the phenotype "neurodevelopmental disorder with or without autism or seizures (NEDAUS, #OMIM: 619239)." This study aimed to present the first Turkish patient with a NEDAUS phenotype exhibiting novel clinical and genotypic findings. CASE PRESENTATION: A 7-year-old patient with seizure, speech delay, decreased eye contact, and autistic behaviors was referred to our clinic. The patient was evaluated through clinical examination, laboratory tests, and imaging studies. Physical examination revealed extremity findings (brachydactyly, tapering fingers). Single whole-exome sequencing analysis was performed for clinical diagnosis. A novel missense variant, c.368T>A (p.Leu123Gln) in , was discovered in the patient. Additionally, computational studies were employed to gain structural and mechanistic insights into the putative damaging impact of the variant. Computational analyses indicated that the p.Leu123Gln substitution may affect the stability and binding behavior of cullin-3. The detected variant was confirmed by the Sanger method and screened in family members by the same method and was found to be de novo. CONCLUSION: By presenting the first Turkish case of a novel missense variant with a CUL3-related NEDAUS phenotype, this study contributes to the expansion of the genotypic and phenotypic spectrum of the disease.
Coexistence of Rare Genetic Disorders in a Consanguineous Family: Case Study of KLHL24-Related Hypertrophic Cardiomyopathy and Char Syndrome.
Linnenkamp BDW, Lacerda Pires LV, Stephan BO … +5 more , Vilalva KH, Lombardi Peres de Carvalho M, Vicente Pereira Lipari LF, Fernandes F, Krieger JE
Mol Syndromol · 2025 Apr · PMID 40176835 · Full text
INTRODUCTION: Physicians often search for a single underlying cause that explains all of a patient's signs and symptoms. However, evidence from the literature suggests that the concurrent presence of two rare diseases, a...
INTRODUCTION: Physicians often search for a single underlying cause that explains all of a patient's signs and symptoms. However, evidence from the literature suggests that the concurrent presence of two rare diseases, although uncommon, poses significant diagnostic challenges. Precision medicine is increasingly important in these scenarios, enabling more rapid diagnosis and tailored treatments. CASE PRESENTATION: This report discusses a patient involving a consanguineous Brazilian family, where two sisters are diagnosed with autosomal recessive -related hypertrophic cardiomyopathy. Additionally, one sister is diagnosed with Char syndrome due to a deletion. CONCLUSION: This case underscores the possibility that multiple rare genetic disorders can coexist, contributing to complex clinical phenotypes. Whole-exome sequencing proves to be a critical tool in identifying the genetic underpinnings of such complex cases, facilitating precise diagnosis and genetic counseling. The discovery of a homozygous variant further broadens the known mutation spectrum and underscores its significance in autosomal recessive hypertrophic cardiomyopathy.
Influence of the IDOL Gene Variants on Low-Density Lipoprotein Cholesterol Levels in Turkish Patients with Familial Hypercholesterolemia.
Duymus F, Kocak N, Özdemir EM … +3 more , Esin D, Körez MK, Cora T
Mol Syndromol · 2025 Apr · PMID 40176834 · Full text
INTRODUCTION: The inducible degrader of low-density lipoprotein (IDOL) receptor, an E3 ubiquitin ligase, was recently identified as a regulator of the LDL receptor (LDLR) pathway. Shortly, IDOL stimulates LDLR degradatio...
INTRODUCTION: The inducible degrader of low-density lipoprotein (IDOL) receptor, an E3 ubiquitin ligase, was recently identified as a regulator of the LDL receptor (LDLR) pathway. Shortly, IDOL stimulates LDLR degradation through ubiquitination. However, the association of gene variants with plasma lipid levels is controversial. No previous study in the Turkish population has reported the relationship between variants of the gene and low-density lipoprotein cholesterol (LDL-C) levels. Our study aims to investigate the effects of genetic variants in the human IDOL gene, which may be a therapeutic target in human cholesterol metabolism, on LDL-C levels. METHODS: We sequenced all coding, critical intronic, and untranslated regions of the IDOL gene in 125 controls (77 women, 48 men) and 125 patients (64 women, 61 men) with definite or probable familial hypercholesterolemia (FH) according to the criteria of the Dutch Lipid Clinic Network, in whom no pathogenic/likely pathogenic LDLR variants are present. RESULTS: We identified 12 different IDOL gene variants, including the p.(N342S) and p.(G51S), whose association with LDL-C levels has been investigated, and classified them into common and rare variants. A rare variant p.(G51S) was only detected in patients the patient group. We compared the minor allele frequency (MAF) distribution of common variants between patient and control groups and examined the association of their genotypic distribution with plasma LDL-C levels using genetic models (dominant, recessive, overdominant, codominant). There was no statistically significant difference in the parameters of the patient and control groups ( > 0.05). CONCLUSION: Our findings suggest that the common IDOL variants we identified do not associate with the LDL-C level in the Turkish population. Rare variants that were not found to be statistically significant in our study, should be emphasized, and supported with further research.
Clinical and Radiological Profile of Nine Patients with Metachromatic Leukodystrophy.
Kasapkara ÇS, Civelek Ürey B, Bilginer Gürbüz B … +10 more , Küçükçongar Yavaş A, Keçeli AM, Öncül Ü, Gündüz M, Biberoğlu G, Çıtak Kurt AN, Gürkaş E, Kılıç E, Güleç Ceylan G, Özbek NY
Mol Syndromol · 2025 Apr · PMID 40176833 · Full text
INTRODUCTION: Metachromatic leukodystrophy (MLD) is a rare, demyelinating, autosomal recessive lysosomal storage disease caused by a deficiency in the arylsulfatase A enzyme (ASA), which is encoded by gene. A lack of AS...
INTRODUCTION: Metachromatic leukodystrophy (MLD) is a rare, demyelinating, autosomal recessive lysosomal storage disease caused by a deficiency in the arylsulfatase A enzyme (ASA), which is encoded by gene. A lack of ASA activity results in an accumulation of sulfatides in the myelin sheaths of both the central and peripheral nervous systems, leading to developmental and neurocognitive progressive deterioration that can be observed in all age groups. METHODS: We present a total of 9 patients with MLD with an average age of 61 months, whose clinical, laboratory and cranial magnetic resonance imaging findings were evaluated, and who underwent an gene molecular analysis. RESULTS: Of the 9 patients, 7 had the late infantile form of the condition, 2 had the juvenile form, and 3 were identified through family screening. The median age at diagnosis was 30 months (min 3-max 73 months), the mean ASA activity value was 2 nmol/h/mgprt and the median cranial MR imaging severity score was 10 (min 5-max 18). The grey and white matter volumes of all patients, evaluated using volBrain software, were within the normal range. At an average age of 48 months, the late-infantile MLD patients were unable to control any body part. CONCLUSIONS: Hematopoietic stem cell transplantation (HSCT), a treatment option for both the juvenile and adult forms of MLD in asymptomatic or early symptomatic patients, was performed on two of the asymptomatic and early symptomatic patients, and post-HSCT ASA activity settled within the normal range and their developmental milestones stabilized. It is important to diagnose MLD in the asymptomatic period and newborn screening can support early diagnosis.
A Novel Splice Site Variant in Gene in Multiple Affected NEM8 Family Members Who Present Phenotypic Variability.
Sönmez B, Kocabey M, Polat Aİ … +8 more , Gürsoy S, Karaoğlu P, Rita Horvath, Schon KR, Ülgenalp A, Yiş U, Çağlayan AO, Giray Bozkaya Ö
Mol Syndromol · 2025 Feb · PMID 39911178 · Full text
INTRODUCTION: Nemaline myopathy (NEM) is a heterogeneous muscle disease, which usually presents with hypotonia and muscle weakness. Biallelic pathogenic variants of gene cause severe form of NEM (NEM8), which leads to a...
INTRODUCTION: Nemaline myopathy (NEM) is a heterogeneous muscle disease, which usually presents with hypotonia and muscle weakness. Biallelic pathogenic variants of gene cause severe form of NEM (NEM8), which leads to a wide range of symptoms, including hypotonia, muscle weakness, joint contractures and fractures. Nemaline bodies in muscle fiber are characteristic findings of the disease. CASE PRESENTATION: Here, we presented three affected individuals in a family with variable phenotypes, in whom the same novel splice-site variant in gene (c.1607+3A>T) was detected. DISCUSSION: This study expanded the spectrum of genotype and phenotype of NEM8, and emphasized that molecular genetic tests are highly valuable in diagnosis of patients with inconclusive muscle biopsy results.
A Case of Opsismodysplasia with a Novel Variant.
Daşar T, Aypar E, Utine GE … +1 more , Şimşek-Kiper PÖ
Mol Syndromol · 2025 Feb · PMID 39911177 · Full text
INTRODUCTION: Opsismodysplasia is a rare autosomal recessive genetic skeletal disorder characterized by short stature, short limbs, small hands and feet, delayed bone age, severe platyspondyly, metaphyseal cupping, and f...
INTRODUCTION: Opsismodysplasia is a rare autosomal recessive genetic skeletal disorder characterized by short stature, short limbs, small hands and feet, delayed bone age, severe platyspondyly, metaphyseal cupping, and facial dysmorphism. Opsismodysplasia is caused by biallelic variants in the gene. Only 38 patients with a confirmed molecular diagnosis have been reported so far. CASE PRESENTATION: We present a 9-month-old male patient who was referred to our clinic with a suspicion of mucopolysaccharidoses due to facial features and radiographic findings, but urine glycosaminoglycans were within normal ranges. Audiologic and ophthalmologic assessments, transfontanelle ultrasound, and echocardiography were all normal. A renal cortical cyst with a diameter of 33 × 28 mm was detected in abdominal ultrasound. He had dysmorphic findings including relative macrocephaly, midface hypoplasia, depressed nasal bridge, anteverted nostrils, long philtrum, small hands and feet, and brachydactyly. His length was 63 cm (-3.7 SD) and his arm span was 58 cm. Delayed bone age, short metacarpals and phalanges, wide and irregular metaphysis, platyspondyly, anterior beaking of the vertebrae, T12 vertebral hypoplasia, and acetabular dysplasia were noted on X-rays. Exome sequencing revealed a novel homozygous c.147C>G (p.Ser49Arg) variant in . CONCLUSION: Opsismodysplasia is an extremely rare skeletal disorder, and with this case, we further expand the clinical and molecular spectrum of opsismodysplasia.
Homozygous Intragenic Deletion in in Siblings with Primary Microcephaly.
Singh SM, Maurya RK, Moirangthem A
Mol Syndromol · 2025 Feb · PMID 39911176 · Full text
INTRODUCTION: Primary microcephaly is genetically heterogeneous. Despite the rapid evolution of scientific information and bioinformatic tools, etiology remains elusive in more than half of the affected population. A sub...
INTRODUCTION: Primary microcephaly is genetically heterogeneous. Despite the rapid evolution of scientific information and bioinformatic tools, etiology remains elusive in more than half of the affected population. A substantial fraction of these undiagnosed cases is anticipated to have large structural variations in one of the causative genes. This class of variations has been difficult to detect by exome sequencing. CASE PRESENTATION: We report a sibling pair with global developmental delay, microcephaly, and brain abnormalities who were recruited under the Indian Undiagnosed Disease Program (I-UDP) for further evaluation after an uninformative initial exome sequencing. CONCLUSION: Copy number analysis using whole genome sequencing data detected a large homozygous deletion of 9.78 kb encompassing exon 1 to exon 3 of (OMIM*613583). These results were further validated by performing comparative quantification of the copy number of deleted exons in both siblings and parents.
A Novel Variant in a Female Patient with Neutral Lipid Storage Disease with Myopathy and Hypogonadotropic Hypogonadism.
Şenol HB, Kısa PT, Kulu B … +3 more , Ören H, Arslan N, Yiş U
Mol Syndromol · 2025 Feb · PMID 39911175 · Full text
BACKGROUND: Neutral lipid storage disease with myopathy (NLSDM) is a rare autosomal recessive disorder characterized by aberrant triacylglycerol metabolism due to mutations in the () gene. CASE PRESENTATION: This report...
BACKGROUND: Neutral lipid storage disease with myopathy (NLSDM) is a rare autosomal recessive disorder characterized by aberrant triacylglycerol metabolism due to mutations in the () gene. CASE PRESENTATION: This report presents a case study of a 14-year-old female patient exhibiting symptoms of NLSDM, including recurrent abdominal pain, fatigue, leg pain, and hepatosteatosis. Diagnostic investigations revealed elevated creatinine kinase levels, myopathic findings on electromyography, magnetic resonance imaging findings showing gluteal involvement and Jordans' bodies on peripheral smear. Clinical exome panel showed homozygous of c.496G>C p.Asp166His (NM_020376.4) variant. The clinical manifestations, diagnostic challenges, and implications of this novel variant are discussed in the context of current literature. Hypogonadotropic hypogonadism was confirmed in this patient after eliminating possible underlying causes. This was a novel manifestation, and hormone replacement therapy was planned. CONCLUSION: This case underscores the significance of genetic testing in elucidating the molecular basis of NLSDM and emphasizes the necessity of comprehensive clinical evaluation for accurate diagnosis and management.
Kabuki Syndrome: Case Report of Severe Prenatal Midface Hypoplasia (Binder Phenotype), due to a Novel Variant in the Gene.
Gatsis A, Alvanou M, Christidou E … +6 more , Demertzidou E, Kontou A, Stathopoulou T, Sarafidis K, Sotiriadis A, Ververi A
Mol Syndromol · 2025 Feb · PMID 39911174 · Full text
INTRODUCTION: Kabuki syndrome (KS) is a rare genetic disorder with a prevalence of 1/86,000-1/32,000. Pathogenic variants in the and genes are responsible for the majority of KS cases and are inherited in an autosomal...
INTRODUCTION: Kabuki syndrome (KS) is a rare genetic disorder with a prevalence of 1/86,000-1/32,000. Pathogenic variants in the and genes are responsible for the majority of KS cases and are inherited in an autosomal dominant and X-linked manner, respectively. Despite KS being genetically pleiotropic, specific phenotypic features, such as hypotonia, developmental disorders, mental retardation, dermatoglyphic and facial abnormalities, are widely manifested among patients with KS. Only few prenatal findings have been associated with KS so far. CASE PRESENTATION: This report highlights an interesting and infrequent case of a neonate with severe midface hypoplasia and multiple congenital anomalies, which were noted on the 2nd trimester antenatal scan. The degree of hypoplasia was indicative of chondrodysplasia punctata, but there was no relevant pregnancy history or other features of a skeletal dysplasia. The pregnancy was complicated by preterm premature rupture of membranes. The neonate was born at 27 weeks of gestation and died 16 days later, due to complications of prematurity. Whole exome sequencing identified a novel de novo pathogenic variant. CONCLUSION: Although midface hypoplasia has been previously reported in individuals with KS, the severity noted in the index individual is an unusual feature of the syndrome.
A Novel Loss-of-Function Variant in COL4A3 in a Consanguineous Moroccan Family Displaying the Alport Syndrome with Variable Clinical Expression.
Taroua O, Askander O, Rhou H … +1 more , Bouhouche A
Mol Syndromol · 2025 Feb · PMID 39911173 · Full text
INTRODUCTION: Alport syndrome (AS) is a rare genetic disorder characterized by abnormalities in the kidneys, ears, and eyes. Its clinical presentation typically manifests in childhood or adolescence and varies widely amo...
INTRODUCTION: Alport syndrome (AS) is a rare genetic disorder characterized by abnormalities in the kidneys, ears, and eyes. Its clinical presentation typically manifests in childhood or adolescence and varies widely among affected individuals, ranging from isolated hematuria to end-stage renal disease. The genetic causes of AS primarily involve mutations in the genes encoding type IV collagen , , and , which play essential roles in maintaining the structural integrity of the glomerular basement membrane in the kidney, the cochlea, and the retina. They can be transmitted in autosomal dominant, autosomal recessive, and X-linked recessive. CASE PRESENTATION: Here we report a Moroccan consanguineous family with an 18-year-old girl who presented with advanced renal failure and microscopic hematuria. Her audiometry revealed hearing impairment. Urinalysis performed in all the asymptomatic family members showed microscopic hematuria in the mother and younger sister, while computed tomography excluded a urologic cause. Using next-generation sequencing analysis, we identified in the proband a nonsense homozygous variant in the gene (c.4114C>T, p.Gln1372Ter) that was never reported in the literature, and which is considered pathogenic according to the ACMG classification. Segregation analysis in the family showed that the parents were heterozygous like the elder brother, whereas the younger sister was mutated homozygous, and the other brother was homozygous normal. CONCLUSION: We report a novel nonsense pathogenic variant in that expends the allelic spectrum in AS. Clinical exploration and genetic testing of all the family members revealed intrafamilial clinical variability, suggesting a pseudo-dominant inheritance and a reduced penetrance.
A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
Bulut G, Turgut GT, Toksoy G … +4 more , Altunoğlu U, Aslanger AD, Uyguner ZO, Karaman B
Mol Syndromol · 2025 Feb · PMID 39911172 · Full text
INTRODUCTION: Sandestig-Stefanova syndrome (MIM:618804) is characterized by pre- and postnatal microcephaly, trigonocephaly, bilateral congenital cataracts, microphthalmia, cleft lip and palate or high-arched palate, cam...
INTRODUCTION: Sandestig-Stefanova syndrome (MIM:618804) is characterized by pre- and postnatal microcephaly, trigonocephaly, bilateral congenital cataracts, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, periventricular white matter loss, thin corpus callosum, and delayed myelination. Bi-allelic loss-of-function variants in the (MIM:615587) gene are implicated in the etiology. CASE PRESENTATION: Our patient, born to consanguineous parents, presented with tetralogy of Fallot, bilateral congenital cataracts, hydrocephalus, a bifid uvula, a right pelvic kidney, hepatomegaly, facial feature findings, and a history of a similarly affected ex-sibling. Whole exome sequence analysis in the index case revealed a novel homozygous variant NM_015354.2: c.124C>T/p.(Arg42Ter) in the gene. CONCLUSION: This study describes a new patient with Sandestig-Stefanova syndrome harboring a novel pathogenic variant in the gene.
PACS2, PACS1, and VACTERL: A Clinical Overlap.
Massey H, Tennant S, Dean J … +1 more , DDD study
Mol Syndromol · 2025 Feb · PMID 39911171 · Full text
INTRODUCTION: Whole-exome sequencing has led to the discovery of new genes involved in developmental delay. Two of these are the evolutionary linked proteins phosphofurin acidic cluster sorting protein 1 (PACS1) and phos...
INTRODUCTION: Whole-exome sequencing has led to the discovery of new genes involved in developmental delay. Two of these are the evolutionary linked proteins phosphofurin acidic cluster sorting protein 1 (PACS1) and phosphofurin acidic cluster sorting protein 2 (PACS2), which function as metabolic switches. We present a case of a patient with the previously described PACS2 c.624G>A; p.Glu209Lys variant, with distinct clinical features, suggesting an overlap between the two conditions. CASE PRESENTATION: The patient presented with infantile epilepsy, developmental delay, and cerebellar hypoplasia previously described with PACS2. However, he also had novel features not noted in the literature before; this included anal atresia, tetralogy of Fallot, and vertebral abnormalities. This constellation of features had given him a label of VACTERL. CONCLUSION: Cardiac abnormalities are more commonly seen in PACS1 variants, and this case strengthens the phenotypic similarities between the two conditions. We also explore the genetic mechanisms causing the cardiac and anal anomalies seen in our patient and suggest the PACS2 disease spectrum should be expanded.
Expression of Autophagy-Related Proteins in Microlissencephaly Associated with a Novel Variant in the Gene.
Yalçın HY, Karabay U, Cinleti T … +4 more , Teke Kısa P, Eğrilmez MY, Ayaz A, Aydın N
Mol Syndromol · 2025 Feb · PMID 39911170 · Full text
INTRODUCTION: Microlissencephaly is a subtype of congenital microcephaly characterized by extreme microcephaly with simplified gyral pattern. Other brain malformations may accompany it. encodes a multi-domain transmembr...
INTRODUCTION: Microlissencephaly is a subtype of congenital microcephaly characterized by extreme microcephaly with simplified gyral pattern. Other brain malformations may accompany it. encodes a multi-domain transmembrane protein that is predominantly expressed in the brain and is thought to play a role in endolysosomal trafficking and autophagy. METHODS: We reported two siblings with microlissencephaly born to consanguineous Turkish parents and reviewed all previously reported patients with variants presenting with severe microcephaly accompanied by congenital brain malformations. Whole-exome sequencing was performed on both siblings. Sanger DNA sequencing was performed on the patients' parents. We also examined LC3, p62, and Beclin 1 mRNA and protein expression levels from blood samples of both siblings using real-time PCR and Western blotting, respectively. RESULTS: Whole-exome sequencing revealed a novel biallelic c.4157+5G>A splice variant in the gene in both siblings. In our study, LC3, p62, and Beclin 1 mRNA expression levels were high, LC3 protein expression level was also high and p62 and Beclin 1 protein expression levels were low. CONCLUSION: High LC3 and low p62 protein expression levels supported studies concluding that inhibits autophagy through PI3KC3 inhibition, while low Beclin 1 protein expression level supported studies concluding that autophagy is suppressed in case of loss of function variants in the gene. We suggest that due to its role in endolysosomal trafficking, -related diseases should be included in vesicular trafficking disorders.
Kabuki Syndrome and Charcot-Marie-Tooth Disease Co-Occurrence: Unique Case with Novel Variant.
Kablan A, Aru EE
Mol Syndromol · 2025 Feb · PMID 39911169 · Full text
INTRODUCTION: Kabuki syndrome (KS) is a rare syndrome, characterized by dysmorphic features, congenital abnormalities, and developmental problems. The primary genetic causes are variants in the and genes. There are few...
INTRODUCTION: Kabuki syndrome (KS) is a rare syndrome, characterized by dysmorphic features, congenital abnormalities, and developmental problems. The primary genetic causes are variants in the and genes. There are few KS patients with variants, especially in Turkey. Charcot-Marie-Tooth (CMT) disease, with various subtypes, is the most common inherited peripheral neuropathy. CASE PRESENTATION: We present a case of a 7-year-old girl with characteristic dysmorphic features, neonatal hypotonia, developmental delay, and short stature. Exome sequencing revealed a novel heterozygous variant in , along with a concurrent suspected diagnosis of CMT disease with CNV analysis, not previously reported in the literature. duplication was later confirmed in the patient and symptomatic mother with MLPA test. CONCLUSION: We report a unique case of dual diagnosis with a novel de novo heterozygous variant in and duplication in the same patient, highlighting the additive use of exome sequencing for CNVs and, moreover, unraveling the complexity of rare diseases, particularly when multiple conditions coexist.
A Unique Derivative Chromosome 4 with a Predominant 4p16.3 Microduplication Phenotype and a Literature Review.
Mekkawy MK, Kamel AK, Refaat KM … +6 more , Madian A, Issa M, Abd Allah SG, Eid OM, Zaki MS, Mohamed AM
Mol Syndromol · 2025 Feb · PMID 39911168 · Full text
INTRODUCTION: Constitutional structural abnormalities affecting chromosome 4 result in variable distinct phenotypic traits including duplication 4p syndrome, deletion 4p or Wolf-Hirschhorn syndrome (WHS), deletion 4q and...
INTRODUCTION: Constitutional structural abnormalities affecting chromosome 4 result in variable distinct phenotypic traits including duplication 4p syndrome, deletion 4p or Wolf-Hirschhorn syndrome (WHS), deletion 4q and duplication 4q syndromes. Complex rearrangements involving both chromosome 4 arms are very rarely reported with different break points occurring within regions of 4p13-p16 and 4q32-35. They most commonly occur in familial cases due to parental pericentric inversion resulting in a recombinant chromosome 4 "rec(4)." The clinical picture is dependent on the size and type of copy number imbalance and the genes involved. METHODS: We report on a female patient with delayed developmental milestones and lower limb anomalies, who carried a de novo unique type of complex rearrangement affecting both chromosome 4 arms, diagnosed by karyotype and fluorescence in situ hybridization analysis and chromosomal microarray (CMA). RESULTS: The chromosome 4 rearrangement involved three copy number alterations, consisting of a terminal 1.17 Mb 4p16.3 deletion with a contiguous proximal 1.8 Mb 4p16.3 duplication, including the Wolf-Hirschhorn critical (WHSC) region, and an inverted 27 Mb terminal 4q32-35.2 duplication attached to terminal 4p. The patient's predominant phenotype was consistent with 4p16.3 microduplication syndrome. The rearrangement occurred as a de novo abnormality, and thus it was designated as a derivative chromosome 4. To the best of our knowledge, this complex type of chromosome 4 rearrangement has not been reported so far. CONCLUSION: The present report adds to the scarce 4p16.3 microduplication syndrome reports and emphasizes the role of WHSC region in the syndromic phenotype. It also reveals the importance of CMA in detecting subtle copy number variations (CNVs) that could be dominantly reflected on the phenotype, which is very important in patients' management and family counselling.
Key Clinical and X-Ray Characteristics for the Diagnosis of Kenny-Caffey Syndrome Types 1 and 2.
Simsek E, Eren SE, Cayir A … +3 more , Tokur O, Cilingir O, Simsek T
Mol Syndromol · 2025 Feb · PMID 39911167 · Full text
INTRODUCTION: Kenny-Caffey syndrome (KCS) is a rare syndrome characterized by short stature, hypoparathyroidism, eye abnormalities, and skeletal dysplasia. Two types of KCS result from pathogenic variants in the tubulin-...
INTRODUCTION: Kenny-Caffey syndrome (KCS) is a rare syndrome characterized by short stature, hypoparathyroidism, eye abnormalities, and skeletal dysplasia. Two types of KCS result from pathogenic variants in the tubulin-specific chaperone E () gene and the family with sequence similarity 111 member A () gene, respectively. CASE PRESENTATION: In this study, we present 4 patients from three different families exhibiting facial dysmorphism, postnatal growth retardation, short stature, delayed bone age, cortical thickening and medullary stenosis of the bones, and hypoparathyroidism. Two of these cases were diagnosed with growth hormone (GH) deficiency and underwent GH therapy, highlighting the response to GH treatment in KCS. Three consanguineous cases of KCS type 1 possess a homozygous variant c.155_166del in the gene, and 1 patient with KCS type 2 has a de novo pathogenic variant c.1706G>A (p.Arg569His) in the gene. CONCLUSIONS: Our findings suggest that prenatal and postnatal growth failure is a prominent characteristic of this syndrome, with KCS types 1 and 2 showing overlapping features.
A Novel Homozygous Variant in Gene in a Patient with Developmental Deficits.
Shankarappa B, Prasad VP, Kumar S … +10 more , Rao RS, Royal AB, Swamy M, Prasad P, Niranjana Murthy AS, Ganesh S, Viswanath B, Jain S, Purushottam M, Thyloth M
Mol Syndromol · 2025 Feb · PMID 39911166 · Full text
BACKGROUND: Oral-facial-digital syndrome (OFDS) type 6 is a rare subtype of Joubert syndrome characterized by orofacial anomalies and polydactyly with neurological features of Joubert syndrome. This rare syndrome is divi...
BACKGROUND: Oral-facial-digital syndrome (OFDS) type 6 is a rare subtype of Joubert syndrome characterized by orofacial anomalies and polydactyly with neurological features of Joubert syndrome. This rare syndrome is divided into thirteen subtypes, all of which demonstrate autosomal recessive inheritance, except for OFDS type 1 which demonstrates X-linked dominant inheritance. CASE PRESENTATION: A 19-year-old man with mild developmental delay was brought to a rural community clinic, as he had become irritable and angry, in the recent past. There was no history of prior medical conditions. In view of orofacial anomalies, and developmental deficits, a genetic analysis was requested. Karyotype analysis revealed a normal male karyotype (46,XY) in all 30 metaphase spreads analyzed. No numerical or structural chromosomal abnormalities were observed. Clinical exome sequencing and chromosomal microarray detected a variant of uncertain significance in exon 5 of gene c.365T>G (p.Val122Gly) leading to substitution of Glycine for Valine. This was confirmed by Sanger sequencing. Parents were heterozygous, and the unaffected sibling was homozygous for the wild-type allele. This variant has not been reported earlier in the mutation databases or gnomAD. Runs of homozygosity (ROH) analysis showed a 3.2 Mb ROH around the gene in the proband, which was absent in both parents and the unaffected sibling. CONCLUSION: We find a novel homozygous mutation in the gene in a patient of non-consanguineous parentage with atypical orofacial features. This suggests that potentially deleterious, rare variants may occur in the heterozygous state in the population. Hence, sequencing of population samples might help understand the genetic epidemiology of rare syndromes.
Clinical and Molecular Cytogenetic Characterization of 2 Sibling Cases with 17q25 Duplication due to Unbalanced Translocation.
Chen N, Zeng W, Luo Y … +1 more , Dong M
Mol Syndromol · 2024 Dec · PMID 39634249 · Full text
INTRODUCTION: Partial 17q duplication is a rare chromosome abnormality. Features include severe psychomotor retardation, intellectual disability, facial dysmorphism, proximal limb shortness, and hyperlaxity of limb joint...
INTRODUCTION: Partial 17q duplication is a rare chromosome abnormality. Features include severe psychomotor retardation, intellectual disability, facial dysmorphism, proximal limb shortness, and hyperlaxity of limb joints. CASE PRESENTATION: The proband is a 7-year and 4-month-old boy with developmental delay, facial abnormality, joint laxity and scoliosis, ventriculomegaly, hydrocephalus, hypophosphatemia, and squint, while his older brother is a fetus who was aborted at 33rd week of gestation because of multiple malformations including ventriculomegaly and moderate hydrocephalus. Both siblings have features such as ventriculomegaly and hydrocephalus. CONCLUSION: Here, we report 2 sibling cases with 17q25 duplication from a maternal translocation t(14;17). Our findings expanded the clinical spectra and described the fetal phenotype of 17q25 microduplication.
Mutation Case Report and Literature Review.
Bayrak H, Sezer A, Kılıç M
Mol Syndromol · 2024 Dec · PMID 39634248 · Full text
INTRODUCTION: Mutations in the RMND1 gene that cause defects in the mitochondrial respiratory chain result in a highly variable phenotypic presentation. The protein required for meiotic nuclear division 1 homolog (RMND1)...
INTRODUCTION: Mutations in the RMND1 gene that cause defects in the mitochondrial respiratory chain result in a highly variable phenotypic presentation. The protein required for meiotic nuclear division 1 homolog (RMND1) is localized to the inner mitochondrial membrane and is encoded by the nuclear genome. CASE PRESENTATION: We report a new patient from a consanguineous family who was severely affected by a previously described combined oxidative phosphorylation deficiency 11 and was treated rapidly due to early diagnosis. METHODS: We also included patients with RMND1 mutation in the literature. We analyzed the epidemiological, clinical, laboratory, and genetic data of a total of 49 patients (98 alleles) in the literature, including our patient. We summarized all previously published patients and focused on the importance of early diagnosis. RESULTS: The most common variant in patients with RMND1 mutation was c.713A>G (p.Asn238Ser). Mortality was significantly lower in patients with homozygous and compound heterozygous c.713A>G (p.Asn238Ser) mutations ( < 0.001). The second most common mutation was c1349G>C (p.*450Serext*31), which was reported in 11 patients (22.4%). Cardiac involvement and mortality were more common in patients with homozygous c.1349G>C (p.*450Serext*32) mutation ( = 0.008 and 0.008, respectively). CONCLUSION: In this study, the effect of cardiac involvement on mortality in RMND1 mutation was shown for the first time. We reported that mortality was lower in the c.713A>G (p.Asn238Ser) mutation. Furthermore, mortality was more common in the c.1349G>C (p.*450Serext*32) mutation. These findings have not been previously reported in the literature. They are reported for the first time in this study.
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