SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype.

Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is the unifying mechanistic theme of the RASopathies, a family of disorders affecting development and growth. Pathogenic variants in more than 20 genes have been causally linked to RASopathies, the majority having a dominant role in promoting enhanced signaling. Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome. Homozygosity for three different variants-c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95)-were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behavior. When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs∗95) documented an increased and prolonged activation of the MAPK cascade in response to EGF stimulation. Morpholino-mediated knockdown of spred2a and spred2b in zebrafish induced defects in convergence and extension cell movements indicating upregulated RAS-MAPK signaling, which were rescued by expressing wild-type SPRED2 but not the SPRED2Leu381Hisfs∗95 protein. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome. These features, in part, characterize the phenotype of Spred2-/- mice. Our findings identify the second recessive form of Noonan syndrome and document pleiotropic consequences of SPRED2 loss of function in development.

HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia.

The congenital bone marrow failure syndrome Diamond-Blackfan anemia (DBA) is typically associated with variants in ribosomal protein (RP) genes impairing erythroid cell development. Here we report multiple individuals with biallelic HEATR3 variants exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability. These variants destabilize a protein whose yeast homolog is known to synchronize the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5), which are both critical for producing ribosomal subunits and for stabilizing the p53 tumor suppressor when ribosome biogenesis is compromised. Expression of HEATR3 variants or repression of HEATR3 expression in primary cells, cell lines of various origins, and yeast models impairs growth, differentiation, pre-ribosomal RNA processing, and ribosomal subunit formation reminiscent of DBA models of large subunit RP gene variants. Consistent with a role of HEATR3 in RP import, HEATR3-depleted cells or patient-derived fibroblasts display reduced nuclear accumulation of uL18. Hematopoietic progenitor cells expressing HEATR3 variants or small-hairpin RNAs knocking down HEATR3 synthesis reveal abnormal acceleration of erythrocyte maturation coupled to severe proliferation defects that are independent of p53 activation. Our study uncovers a new pathophysiological mechanism leading to DBA driven by biallelic HEATR3 variants and the destabilization of a nuclear import protein important for ribosome biogenesis.

A novel GRK2 variant in a patient with Jeune asphyxiating thoracic dysplasia accompanied by Morgagni hernia.

Skeletal ciliopathies constitute a subgroup of ciliopathies characterized by various skeletal anomalies arising from mutations in genes impacting cilia, ciliogenesis, intraflagellar transport process, or various signaling pathways. Short-rib thoracic dysplasias, previously known as Jeune asphyxiating thoracic dysplasia (ATD), stand out as the most prevalent and prototypical form of skeletal ciliopathies, often associated with semilethality. Recently, pathogenic variants in GRK2, a subfamily of mammalian G protein-coupled receptor kinases, have been identified as one of the underlying causes of Jeune ATD. In this study, we report a new patient with Jeune ATD, in whom exome sequencing revealed a novel homozygous GRK2 variant, and we review the clinical features and radiographic findings. In addition, our findings introduce Morgagni hernia and an organoaxial-type rotation anomaly of the stomach and midgut malrotation for the first time in the context of this recently characterized GRK2-related skeletal ciliopathy.

Further defining the molecular spectrum and long-term follow-up of 17 patients with Dyggve-Melchior-Clausen and Smith-McCort dysplasia type 2.

Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondylo-epi-metaphyseal dysplasias with identical radiological and clinical findings. DMC and SMC type 1 are allelic disorders caused by homozygous or compound heterozygous variants in DYM, while biallelic causative variants in RAB33B lead to SMC type 2. The terminology "skeletal golgipathies" has been recently used to describe these conditions, highlighting the pivotal role of these two genes in the organization and intracellular trafficking of the Golgi apparatus. In this study, we investigated 17 affected individuals (8 males, 9 females) from 10 unrelated consanguineous families, 10 diagnosed with DMC and seven with SMC type 2. The mean age at diagnosis was 9.61 ± 9.72 years, ranging from 20 months to 34 years, and the average height at diagnosis was 92.85 ± 15.50 cm. All patients exhibited variable degrees of short trunk with a barrel chest, protruding abdomen, hyperlordosis, and decreased joint mobility. A total of nine different biallelic variants were identified, with six being located in the DYM gene and the remaining three detected in RAB33B. Notably, five variants were classified as novel, four in the DYM gene and one in the RAB33B gene. This study aims to comprehensively assess clinical, radiological, and molecular findings along with the long-term follow-up findings in 17 patients with DMC and SMC type 2. Our results suggest that clinical symptoms of the disorder typically appear from infancy to early childhood. The central notches of the vertebral bodies were identified as early as 20 months and tended to become rectangular, particularly around 15 years of age. Pseudoepiphysis was observed in five patients; we believe this finding should be taken into consideration when evaluating hand radiographs in clinical assessments. Furthermore, our research contributes to an enhanced understanding of clinical and molecular aspects in these rare "skeletal golgipathies," expanding the mutational spectrum and offering insights into long-term disease outcomes.

Ex vivo disease modelling of Rett syndrome: the transcriptomic and metabolomic implications of direct neuronal conversion.

BACKGROUND: Rett syndrome (RTT) is a rare neurodevelopmental disorder that primarily affects females and is characterized by a period of normal development followed by severe cognitive, motor, and communication impairment. The syndrome is predominantly caused by mutations in the MECP2. This study aimed to use comprehensive multi-omic analysis to identify the molecular and metabolic alterations associated with Rett syndrome. METHODS AND RESULTS: Transcriptomic and metabolomic profiling was performed using neuron-like cells derived from the fibroblasts of 3 Rett syndrome patients with different MECP2 mutations (R168X, P152R, and R133C) and 1 healthy control. Differential gene expression, alternative splicing events, and metabolite changes were analyzed to identify the key pathways and processes affected in patients with Rett syndrome. Transcriptomic analysis showed there was significant down-regulation of genes associated with the extracellular matrix (ECM) and cytoskeletal components, which was particularly notable in patient P3 (R133C mutation), who had non-random X chromosome inactivation. Additionally, significant changes in microtubule-related gene expression and alternative splicing events were observed, especially in patient P2 (P152R mutation). Metabolomic profiling showed that there were alterations in metabolic pathways, particularly up-regulation of ketone body synthesis and degradation pathways, in addition to an increase in free fatty acid levels. Integrated analysis highlighted the interplay between structural gene down-regulation and metabolic shifts, underscoring the adaptive responses to cellular stress in Rett neurons. CONCLUSION: The present findings provide valuable insights into the molecular and metabolic landscape of Rett syndrome, emphasizing the importance of combining omic data to enlighten the molecular pathophysiology of this syndrome.

Delineation of ADPRHL2 Variants: Report of Two New Patients with Review of the Literature.

ADPRHL2 is involved in posttranslational modification and is known to have a role in physiological functions such as cell signaling, DNA repair, gene control, cell death, and response to stress. Recently, a group of neurological disorders due to ADPRHL2 variants is described, characterized by childhood-onset, stress-induced variable movement disorders, neuropathy, seizures, and neurodegenerative course. We present the diagnostic pathway of two pediatric patients with episodic dystonia and ataxia, who later had a neurodegenerative course complicated by central hypoventilation syndrome due to the same homozygous ADPRHL2 variant. We conducted a systematic literature search and data extraction procedure following the Preferred Reporting Items for Systematic Review and Meta-Analysis 2020 statement in terms of patients with ADPRHL2 variants, from 2018 up to 3 February, 2023. In total, 12 articles describing 47 patients were included in the final analysis. Median age at symptom onset was 2 (0.7-25) years, with the most common presenting symptoms being gait problems (n = 19, 40.4%), seizures (n = 16, 34%), ataxia (n = 13, 27.6%), and weakness (n = 10, 21.2%). Triggering factors (28/47; 59.5%) and regression (28/43; 60.4%), axonal polyneuropathy (9/23; 39.1%), and cerebral and cerebellar atrophy with white matter changes (28/36; 77.7%) were the other clues. The fatality rate and median age of death were 44.6% (n = 21) and 7 (2-34) years, respectively. ADPRHL2 variants should be considered in the context of episodic, stress-induced pediatric and adult-onset movement disorders and seizures.

Review of patients with achondroplasia: a single-center's experience with follow-up and associated morbidities.

Achondroplasia (ACH; MIM #100,800), caused by a heterozygous gain of function pathogenic variant in the fibroblast growth factor receptor 3 gene (FGFR3; MIM*134,934), is the most prevalent and most readily identifiable cause of disproportionate short stature that is compatible with life. In addition, individuals with achondroplasia face significant medical, functional, and psychosocial challenges throughout their lives. This study assessed associated morbidities in patients with achondroplasia at a single center in Turkey. In this study, the clinical findings and associated morbidities of a group of patients with achondroplasia (n = 68) with clinical multidisciplinary follow-up at a single center between the years 2005-2023 are evaluated retrospectively. A total of 68 patients, 30 male (44.1%) and 38 female (55.9%), were evaluated. In the majority (84.2%) of patients, shortness of extremities was detected in the prenatal period at an average of 28.7 gestational weeks (± 3.6 SDS) with the aid of ultrasonography. More than half (n = 34/63, 54%) of the patients had a father of advanced paternal age (≥ 35 years). Among the complications, respiratory system manifestations, including obstructive sleep apnea (70%), ear-nose-throat manifestations including adenoid hypertrophy (56.6%) and otitis media (54.7%), neurological manifestations due to foramen magnum stenosis (53.2%), and skeletal manifestations including scoliosis (28.8%), are represented among the most common. The mortality rate was 7.3% (n = 5/68).Conclusion: This study not only represents the first retrospective analysis of the associated morbidities of patients with achondroplasia from a single center in Turkey but also will provide a reference point for future studies.

A novel biallelic CRIPT variant in a patient with short stature, microcephaly, and distinctive facial features.

Primordial dwarfism (PD) is one of a highly heterogeneous group of disorders characterized by severe prenatal/postnatal growth restriction. Defects in various pathways such as DNA repair mechanism, impaired centrioles, abnormal IGF expression, and spliceosomal machinery may cause PD including Seckel syndrome, Silver-Russell syndrome. Microcephalic osteodysplastic primordial dwarfism (MOPD) types I/III, II, and Meier-Gorlin syndrome. In recent years with the wide application of exome sequencing (ES) in the field of PD, new genes involved in novel pathways causing new phenotypes have been identified. Pathogenic variants in CRIPT (MIM# 604594) encoding cysteine-rich PDZ domain-binding protein have recently been described in patients with PD with a unique phenotype. This phenotype is characterized by prenatal/postnatal growth restriction, facial dysmorphism, ocular abnormalities, and ectodermal findings such as skin lesions with hyper/hypopigmented patchy areas and hair abnormalities. To our knowledge, only three patients with homozygous or compound heterozygous variants in CRIPT have been reported so far. Here, we report on a male patient who presented with profound prenatal/postnatal growth restriction, developmental delay, dysmorphic facial features, and skin lesions along with the findings of bicytopenia and extensive retinal pigmentation defect. A novel truncating homozygous variant c.7_8delTG; p.(Cys3Argfs*4) was detected in CRIPT with the aid of ES. With this report, we further expand the mutational and clinical spectrum of this rare entity.

Evaluation of polysomnography findings in children with genetic skeletal disorders.

Children with genetic skeletal disorders have variable conditions that can lead to sleep-disordered breathing, and polysomnography is the gold standard for diagnosing this condition. We aimed to review polysomnography findings, to assess the severity of sleep apnea, and to investigate the clinical variables predictive of sleep-disordered breathing in these patients. We retrospectively collected the medical records of patients with genetic skeletal disorders who underwent polysomnography for 5 years. Twenty-seven children with various genetic skeletal disorders, including achondroplasia (14), Crouzon syndrome (3), acromesomelic dysplasia Maroteaux type (3), Apert syndrome (2), osteopetrosis (1), Jeune dysplasia (1), Desbuquois dysplasia (1), acrodysostosis (1), and spondyloepiphyseal dysplasia (1) were enrolled. The median age at the first polysomnography was 58 (1st-3rd quartile: 31-113) months. The overall sleep-disordered breathing results were: 19 (70.3%) had obstructive sleep apneas (OSA) (4 mild, 6 moderate, 9 severe), 2 (7.4%) had central apneas, 4 (14.8%) had nocturnal hypoventilation. There was a significant correlation between non-ambulatory status with both total AHI and OSA (p < 0.001, rho: -0.66/p = 0.04, rho: 0.38, respectively). Nine patients received positive airway pressure titration, and the oAHI values of all returned to the normal range. These patients were started with positive airway pressure treatment. Our cohort showed that the majority of the patients with skeletal dysplasia had sleep apnea syndrome characterised mainly by OSA, highlighting the importance of polysomnography screening for sleep disorders. Positive airway pressure therapy represents an effective treatment for sleep-disordered breathing in those patients.

Biallelic loss-of-function variants in EXOC6B are associated with impaired primary ciliogenesis and cause spondylo-epi-metaphyseal dysplasia with joint laxity type 3.

Spondylo-epi-metaphyseal dysplasias with joint laxity, type 3 (SEMDJL3) is a genetic skeletal disorder characterized by multiple joint dislocations, caused by biallelic pathogenic variants in the EXOC6B gene. Only four individuals from two families have been reported to have this condition to date. The molecular pathogenesis related to primary ciliogenesis has not been enumerated in subjects with SEMDJL3. In this study, we report two additional affected individuals from unrelated families with biallelic pathogenic variants, c.2122+15447_2197-59588del and c.401T>G in EXOC6B identified by exome sequencing. One of the affected individuals had an intellectual disability and central nervous system anomalies, including hydrocephalus, hypoplastic mesencephalon, and thin corpus callosum. Using the fibroblast cell lines, we demonstrate the primary evidence for the abrogation of exocytosis in an individual with SEMDLJ3 leading to impaired primary ciliogenesis. Osteogenesis differentiation and pathways related to the extracellular matrix were also found to be reduced. Additionally, we provide a review of the clinical and molecular profile of all the mutation-proven patients reported hitherto, thereby further characterizing SEMDJL3. SEMDJL3 with biallelic pathogenic variants in EXOC6B might represent yet another ciliopathy with central nervous system involvement and joint dislocations.

Diagnostic distribution and postnatal evaluation of prenatally detected short femur: A single center experience.

Genetic skeletal disorders (GSDs) are clinically and etiologically heterogeneous group of disorders caused by abnormal growth and development of bone and/or cartilaginous tissues. Timely and accurate diagnosis is essential for prevention of significant comorbidities. In this study demographic, parental, prenatal and natal characteristics, and postnatal diagnostic distribution along with follow-up processes of 104 individuals with the finding of "short femur" detected in routine prenatal ultrasonography were evaluated. Of 104 patients, 19 (18.2%) were medically terminated, 12 (11.6%) were deceased during follow-up and 73 (70.2%) were still under follow-up. Diagnostic distribution of 104 patients was as follows: 77 (74%) had GSD, eight (7.7%) had chromosomal disorder, seven (6.7%) were completely normal, and 12 (11.5%) had no definite diagnosis. Long-term follow up evaluation contributed to clinical diagnosis in four patients. When grouped according to Nosology and Classification of GSDs: 2019 revision, the most frequent (n = 30, 38.5%) group was "FGFR3 chondrodysplasia group", followed by "Type 2 collagen group" (n = 7, 9%), and "Osteogenesis imperfecta and decreased bone density group" (n = 5, 6.4%). The finding of prenatally detected "short femur" represents a group of diverse diagnosis with heterogeneous etiology. GSDs are the most common etiology among fetuses with short extremity.

Obstructive sleep apnea in children with Down syndrome: is it possible to predict severe apnea?

The objectives are to explore the demographic and polysomnographic features of children with Down syndrome and to determine the predictive factors associated with severe sleep apnea. A total of 81 children with Down syndrome referred for full-night polysomnography were analyzed. In addition, parental interviews were performed for each child. Data were available for 81 children, with a mean age of 4.8 years. Severe obstructive sleep apnea was determined in 53.1%. Age, sex, exposure to second-hand smoke, clinical findings, anthropometric features, and the presence of comorbidities were not predictors of severe obstructive sleep apnea. Children who were exposed to second-hand smoke had more sleep-related symptoms. Even in children without symptoms, the prevalence of severe obstructive sleep apnea was 40%. Moreover, 86% of parents had no previous information regarding possible sleep breathing disorders in their children. Clinically significant central apnea was present in 10 patients (12.3%).Conclusion: Our results demonstrate that severe obstructive sleep apnea is common in children with Down syndrome, even in children without a history of symptoms of sleep apnea. It is not possible to predict patients with severe apnea; thus, screening of children with Down syndrome beginning from young ages is very important. Central apneas could be a part of the spectrum of sleep abnormalities in Down syndrome.

Further defining the clinical and molecular spectrum of acromesomelic dysplasia type maroteaux: a Turkish tertiary center experience.

Acromesomelic dysplasia type Maroteaux (AMDM, OMIM #602875) is an autosomal recessive disorder characterized by severe short stature, shortened middle and distal segments of the limbs, redundant skin of fingers, radial head subluxation or dislocation, large great toes and cranium, and normal intelligence. Only the skeletal system appears to be consistently affected. AMDM is caused by biallelic loss-of-function variants in the natriuretic peptide receptor B (NPRB or NPR2, OMIM #108961) which is involved in endochondral ossification and longitudinal growth of limbs and vertebrae. In this study, we investigated 26 AMDM patients from 22 unrelated families and revealed their genetic etiology in 20 families, via Sanger sequencing or exome sequencing. A total of 22 distinct variants in NPR2 (14 missense, 5 nonsense, 2 intronic, and 1 one-amino acid deletion) were detected, among which 15 were novel. They were in homozygous states in 19 patients and in compound heterozygous states in four patients. Parents with heterozygous NPR2 variants were significantly shorter than the control. Extra-skeletal abnormalities, including global developmental delay/intellectual disability, nephrolithiasis, renal cyst, and oligodontia were noted in the patient cohort. The high parental consanguinity rate might have contributed to these findings, probably associated with other gene variants. This study represents the largest cohort of AMDM from Turkey and regional countries and further expands the molecular and clinical spectrum of AMDM.

Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: A rare disorder with neurologic regression and skeletal features.

Colony stimulating factor 1 receptor (CSF1R, MIM# 164770) encodes a tyrosine-kinase receptor playing an important role in development of osteoclasts and microglia. Heterozygous CSF1R variants have been known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS, MIM# 221820), an adult-onset leukoencephalopathy characterized by loss of motor functions and cognitive decline. Recently, a new phenotype characterized by brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) with biallelic CSF1R pathogenic variants in the etiology has been described. BANDDOS differs from HDLS by early-onset neurodegenerative changes with additional structural brain abnormalities and skeletal findings resembling dysosteosclerosis (DOS). Described skeletal findings of the disease are highly variable ranging from absence of a skeletal phenotype and milder Pyle disease-like to osteopetrosis and DOS. To date, only a few patients carrying biallelic CSF1R variants have been reported. In this clinical report, we describe three siblings with variable skeletal findings along with neurological symptoms ranging from mild to severe in whom exome sequencing revealed a novel homozygous splice site variant in canonical splice donor site of intron 21 adjacent to an exon, which encoding part of kinase domain of CSF1R along with a review of the literature.

Spondyloepimetaphyseal dysplasia EXTL3-deficient type: Long-term follow-up and review of the literature.

Spondyloepimetaphyseal dysplasia (SEMD) is a group of genetic skeletal disorders characterized by disproportionate short stature, and varying degrees of vertebral, epiphyseal, and metaphyseal involvement of the skeleton. According to the Nosology and classification of genetic skeletal disorders 2019 revision, more than 20 types of SEMD have been identified, and SEMD with immune deficiency, EXTL3 type is one of the newcomers. Affected individuals display variable skeletal abnormalities and neurodevelopmental findings. Liver and kidney cysts have also been reported frequently. Patients may exhibit varying degrees of immune deficiency as well. To date, only 14 patients from 9 unrelated families with SEMD with immune deficiency, EXTL3 type have been reported in the literature. We report a new patient who is currently 15 years old in whom cystic liver lesions were detected in the prenatal period. Disproportionate short stature, mild developmental delay and a T- NK+ B+ immunological profile were detected in the postnatal follow-up. Exome sequence analysis revealed a previously reported homozygous missense variant in exon 3 c.953C > T; p.(Pro318Leu) in EXTL3.

A rare cause of syndromic short stature: 3M syndrome in three families.

3M syndrome is a rare autosomal recessive genetic disorder characterized by severe growth retardation, dysmorphic facial features, skeletal dysplasia, and normal intelligence. Variants in CUL7, OBSL1, and CCDC8 genes have been reported to be responsible for this syndrome. In this study, the clinical and molecular findings of four 3M syndrome cases from three families are presented. All cases had growth retardation, relative macrocephaly, and typical dysmorphic facial features. Their neurological developments were normal. Sequencing of CUL7, OBSL1, and CCDC8 genes revealed two different novel homozygous variants in CUL7 in Families 1 and 3 and a previously reported homozygous pathogenic variant in OBSL1 in Family 2. In conclusion, a comprehensive dysmorphological evaluation should be obtained in individuals presenting with short stature and in such individuals with typical facial and skeletal findings, 3M syndrome should be considered. Our report expands the genotype of 3M syndrome and emphasizes the importance of thorough physical and dysmorphological examination.

A Revisited Diagnosis of Collagen VI Related Muscular Dystrophy in a Patient with a Novel COL6A2 Variant and 21q22.3 Deletion.

The genetic etiology of collagen VI related muscular dystrophies is heterogenous. Genomic deletions in one allele involving COL6A2 or both COL6A1 and COL6A2 unmasking a pathogenic variant in the second nondeleted allele have been described in the etiology. We aimed to report the clinical and molecular findings of a 13-year-old boy with ring chromosome 21 who presented to our clinic with easy fatigability, muscle weakness, and waddling gait. Phenotypic delineation along with chromosomal microarray analysis and DNA sequencing were performed. Affymetrix CytoScan Optima array platform and DNA sequencing revealed a 2,202 kb de novo deletion at 21q22.3, including COL6A1 and COL6A2, and a novel heterozygous variant at position c.2875G > A;p.(Glu959Lys) in COL6A2, respectively. Before his admission to our center, the patient was evaluated for hypotonia elsewhere when he was 15 months old. He was diagnosed with ring chromosome 21 on peripheral blood karyotype analysis; however, no further assessment was performed at that time. He had normal growth with mild dysmorphic facial features, distal laxity, gastrocnemius hypertrophy, proximal muscle weakness, increased lordotic posture with mild flexion contractures at the knees, and gait disturbance. Although the phenotype does not fit into classical Ullrich congenital muscular dystrophies, muscle magnetic resonance imaging (MRI) revealed a complementary pattern consistent with collagen VI related myopathies. Genetic testing confirmed the clinical diagnosis as well. This patient yet represents another example of the effect of large genomic deletions leading to recessive disorders through unmasking a pathogenic variant in the second nondeleted allele.

Atypical Presentation of Sengers Syndrome: A Novel Mutation Revealed with Postmortem Genetic Testing.

INTRODUCTION: Sengers syndrome is an autosomal recessive disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. The causative AGK mutations have been identified with whole exome sequencing. CLINICAL REPORT: We report on a 9-month-old infant with episodic lactic acidosis who died before a definitive diagnosis could be established. Postmortem genomic autopsy revealed a novel homozygous NM_018238: c.1215dupG; p.Phe406Valfs*4 mutation in AGK (OMIM 610345) confirming the diagnosis of Sengers syndrome. CONCLUSION: This report provides further evidence that reverse genetics is a useful approach in patients who do not manifest the hallmark features of known and recognizable syndromes.

Further expanding the mutational spectrum and investigation of genotype-phenotype correlation in 3M syndrome.

3M syndrome is characterized by severe pre- and postnatal growth retardation, typical facial features, and normal intelligence. Homozygous or compound heterozygous mutations in either CUL7, OBSL1, or CCDC8 have been identified in the etiology so far. Clinical and molecular features of 24 patients (23 patients and a fetus) from 19 unrelated families with a clinical diagnosis of 3M syndrome were evaluated and genotype-phenotype correlations were investigated with the use of DNA sequencing, chromosomal microarray, and whole exome sequencing accordingly. A genetic etiology could be established in 20 patients (n = 20/24, 83%). Eleven distinct CUL7 or OBSL1 mutations, among which eight was novel, were identified in 18 patients (n = 18/24, 75%). Ten patients had CUL7 (n = 10/18, 56%) while eight had OBSL1 (n = 8/18, 44%) mutations. Birth weight and height standard deviation scores at admission were significantly (p < 0.05) lower in patients with CUL7 mutation compared to that of patients with OBSL1 mutation. Two patients with a similar phenotype had a de novo 20p13p deletion involving BMP2. No genetic etiology could be established in four patients (n = 4/28, 17%). This study yet represents the largest cohort of 3M syndrome patients from a single center in Turkey. Microdeletions involving BMP2 may cause a phenotype similar to 3M syndrome with some distinctive features. Larger cohort of patients are required to establish genotype-phenotype correlations in 3M syndrome.