Exome Sequencing Analysis and Clinical Features of a Chinese Patient with 3M Syndrome and A Review of Literature

3M syndrome is an autosomal recessive disorder characterized by short stature and skeletal developmental abnormalities. A Chinese girl with 3M syndrome and a novel OBSL1 (obscurin-like 1 gene) variant is presented. The patient is a 2-year-old girl who presented with short stature and had intrauterine growth retardation and low birth weight. Gene analysis revealed compound heterozygote mutations in the OBSL1 gene: c.458dupG (p.L154Pfs*100) and c.427dupG (p.A143Gfs*111). The c.427dupG mutation is novel. The c.458dupG mutation has been documented in five cases, occurring only in Chinese individuals, suggesting ethnic specificity. In cases of children with short stature presenting with intrauterine growth retardation, low birth weight, and skeletal developmental abnormalities, 3M syndrome should be considered. The c.458dupG mutation may be a hotspot mutation in the Chinese population.

To analyze the clinical features of 3M syndrome and effect of growth hormone therapy. Clinical data of four children diagnosed with 3M syndrome by whole exome sequencing at Hunan Children's Hospital from January 2014 to February 2022 were retrospectively analyzed, which included clinical manifestation, results of genetic testing and recombinant human growth hormone (rhGH) therapy. A literature review was also carried our for Chinese patients with 3M syndrome. The clinical manifestations of the 4 patients included severe growth retardation, facial dysmorphism and skeletal malformations. Two patients were found to harbor homozygous variants of CUL7 gene, namely c.4717C>T (p.R1573*) and c.967_993delinsCAGCTGG (p.S323Qfs*33). Two patients were found to harbor 3 heterozygous variants of the OBSL1 gene including c.1118G>A (p.W373*), c.458dupG (p.L154Pfs*1002) and c.690dupC (p.E231Rfs*23), among which c.967_993delinsCAGCTGG and c.1118G>A were unreported previously. Eighteen Chinese patients with 3M syndrome were identified through the literature review, including 11 cases (11/18, 61.1%) carrying CUL7 gene variants and 7 cases (7/18, 38.9%) carrying OBSL1 gene variants. The main clinical manifestations were in keeping with previously reported. Four patients were treated with growth hormone, 3 showed obvious growth acceleration, and no adverse reaction was noted. 3M syndrome has a typical appearance and obvious short stature. To attain accurate diagnosis, genetic testing should be recommended for children with a stature of less than -3 SD and facial dysmorphism. The long-term efficacy of growth hormone therapy for patients with 3M syndrome remains to be observed.

To explore the clinical features, genetic characteristics in a child with Miller-McKusick-Malvaux syndrome (3MS) type 1 caused by CUL7 gene variant. A child diagnosed with 3MS type 1 at the Children's Hospital Affiliated to Zhengzhou University in February 2021 was selected as the subject of this study. Peripheral blood samples were collected from the child and her parents for genomic DNA extraction. Whole exome sequencing (WES) was performed on the child, and Sanger sequencing was used to validate the candidate variants and analyze their pathogenicity. A literature search was conducted using the keywords "3M syndrome" in the China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, and PubMed databases from inception to December 2024. The clinical data of Chinese children with 3MS reported in the literature were summarized. This study was approved by the Medical Ethics Committee of the Children's Hospital Affiliated to Zhengzhou University (Ethics No. 2024-K-020). The child was a 6-year-old and 2-month-old female with facial dysmorphism, skeletal abnormalities, and growth and developmental delay. WES revealed compound heterozygous variants in the CUL7 gene: c.2686G>T (p.E896*) and c.1200delT (p.R401Gfs66). Sanger sequencing confirmed that these two variants were inherited from the child's father and mother, respectively. According to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants, c.2686G>T (p.E896) was classified as a pathogenic (PVS1+PM2_Supporting+PM3), and c.1200delT (p.R401Gfs*66) was classified as a likely pathogenic (PVS1+PM2_Supporting). Based on the literature search strategy, 18 relevant articles were identified, including a total of 32 Chinese cases of 3MS, of which 8 were fetuses. A total of 32 Chinese 3MS cases were included in the literature review, of which 8 were fetuses. The majority of these cases carried variants in the CUL7 gene (20/32, 62.5%) and OBSL1 gene (12/32, 37.5%). The main clinical manifestations included intrauterine or postnatal growth and developmental delay (32/32, 100.0%), triangular facies (27/32, 84.3%), and skeletal abnormalities (21/32, 65.6%). The compound heterozygous variants c.2686G>T (p.E896*) and c.1200delT (p.R401Gfs*66) in the CUL7 gene are likely the genetic cause of 3MS type 1 in the child. For children presenting with facial dysmorphism, skeletal abnormalities, and intrauterine or postnatal growth and developmental delay, 3MS should be considered as a differential diagnosis.

Preterm Infant with Craniofacial Dysmorphic Features and Posture.

Prenatal exome sequencing for fetuses with structural abnormalities: the next step.

Introduction: 3M syndrome is an autosomal recessive disorder characterized by characteristic facial features, severe pre- and postnatal growth restriction (<–4 SDS), and normal mental development. 3M syndrome is genetically heterogeneous. Up to date, causative mutations have been demonstrated in 3 genes, cullin-7 (CUL7), obscurin-like 1 (OBSL1), and coiled coil domain containing protein 8 (CCDC8). Case presentation: Here, we report a patient who was referred to our clinic due to short stature and developmental delay. Physical examination revealed prenatal onset short stature, low birth weight, and normal head circumference. She displayed several dysmorphic facial features in addition to developmental delay and bilateral sensorineural hearing loss. The physical findings were suggestive of 3M syndrome. Genetic assessment revealed a novel homozygous frameshift c.418_419delAC (p.Thr140Cysfs*11) variant in the CUL7 gene and a previously reported pathogenic nonsense homozygous c.942C>A (p.Cys314Ter) variant in the ILDR1 gene. The parents were heterozygous for the same variant. Discussion: 3M syndrome should be considered in the differential diagnosis of patients with short stature and typical facial features even if in the presence of other inconsistent features such as developmental delay. In addition, it is important to take into account the co-occurrence of rare autosomal recessive genetic disorders especially in countries with a high consanguineous marriage rate.

3M syndrome: A Tunisian seven-cases series

Background: 3M syndrome is a rare autosomal recessive disease, characterized by intrauterine and postnatal growth retardation, facial dysmorphism, large head circumference, and skeletal changes, has rarely been reported in the Chinese population. Methods: We describe the clinical manifestations and gene variants in four sporadic cases of 3M syndrome in Chinese individuals from different families. Results: All cases had significant growth retardation, relative macrocephaly, and typical facial features. Exome sequencing revealed that two patients with 3M syndrome had homozygous variants of the CUL7 gene: one novel pathogenic variant and one previously reported pathogenic variant; the other two patients were heterozygous for variants in OBSL1, one of which had not been reported previously. Clinical evaluation indicated that these Chinese patients with 3M syndrome shared similar recognizable features with those reported in patients of other ethnic backgrounds, but not all patients with 3M syndrome in this study had normal development milestones. Two patients underwent recombinant human growth hormone (rhGH) therapy and showed accelerated growth in the first 2years; however, the growth rate slowed in the third year in one case. There were no obvious adverse reactions during rhGH treatment. Conclusion: We report one novel CUL7 and one novel OBSL1 mutation in patients with 3M syndrome. Children with short stature, specific facial features, and physical symptoms should be referred for genetic testing to obtain precise diagnosis and appropriate treatment. The effects of rhGH treatment on adult height requires long-term observation and study in a large sample.

The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)

The presence of two different genetic conditions in the same individual is possible, especially in populations with consanguinity. In this case report, we present the coexistence of Artemis deficiency (OMIM 602450) and Three M (3M) syndrome (OMIM 273750). A 10-months-old male patient with neuromotor developmental delay was evaluated for immunodeficiency due to recurrent respiratory infections diarrhea and oral moniliasis from the age of 1.5 months. He had facial dysmorphism with rotated ears, flat nose and hypertelorism. Neurological examination revealed generalized hypotonia and mental motor delay. Immunological screening of the patient demonstrated mild lymphopenia, hypogammaglobulinemia, reduced number of CD3+ T cells (980 cells/mm3) and CD19+ B cells (35 cells/mm3). He was diagnosed with leaky T-B-NK+ SCID. Exome sequence analysis showed the presence of a homozygous pathogenic DCLRE1C variant [c.194C > T; p.T65I (NM_001033855)] and a homozygous pathogenic variant in OBSL1, a gene associated with 3M syndrome [c.3922C > T; p.R1308X (NM_001173431)]. Our proband died of sepsis and multiple organ failure. This case illustrates that different clinical findings in patients might not be explained with a single genetic defect, and consanguinity increases the change for coexistence of autosomal recessive diseases. Clinicians should consider exome sequencing to identify disease-causing mutations in patients with heterogeneity of clinical findings.

BackgroundSilver-Russell syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction, relative macrocephaly at birth, body asymmetry and typical facial features. Clinical and molecular heterogeneity is described in SRS. Common causes are loss of methylation of the imprinting center 1 in 11p15 and maternal uniparental disomy of chromosome 7. Other genetic alterations include disturbances of imprinted regions in 14q32, 7q32 and 11p15 as well as submicroscopic deletions and duplications. Single nucleotide variants in genes like IGF2, HMGA2, PLAG1, CDKN1C have also been identified in patients with SRS phenotypes. However, routine molecular diagnostics usually focus on 11p15 and chromosome 7, while less frequent causes are not systematically addressed.ResultsHere we report two patients with SRS features in which molecular karyotyping revealed microdeletions in 1q21 and 8q12.1 respectively. In a 3.5-year-old girl with postnatal growth restriction, feeding difficulties, relative macrocephaly and distinct SRS features a 2 Mb deletion in 1q21.1q21.2 was identified. Our second case is a 1.5-year-old boy with intrauterine and postnatal growth restriction, feeding difficulties and distinct facial features with a 77 kb deletion in 8q12.1 affecting PLAG1 as the only protein-encoding gene with known function.ConclusionsThe 1q21 region has not yet been assigned as an SRS region, although six patients with the same deletion and SRS features including relative macrocephaly have been described before. This new case adds to the evidence that distal 1q21 should be annotated as an SRS candidate region. The PLAGL1 alteration is the smallest deletion in 8q12.1 ever reported in a patient with SRS phenotype and it finally confirms that PLAG1 is the SRS causing gene in 8q12.1. To increase the diagnostic yield in patients with suspected SRS, we recommend both molecular karyotyping and next generation sequencing-based approaches.

Intrauterine growth restriction (IUGR) results in dysregulated glucose homeostasis and adiposity in the adult. We hypothesized that with aging, these perturbations will wane, and superimposition of postnatal growth restriction (PNGR) on IUGR [intrauterine and postnatal growth restriction (IPGR)] will reverse the residual IUGR phenotype. We therefore undertook hyperinsulinemic-euglycemic clamp, energy balance, and physical activity studies during fed, fasted, and refed states, in light and dark cycles, on postweaned chow diet-fed more than 17-month aging male IUGR, PNGR, and IPGR vs. control (CON) rat offspring. Hyperinsulinemic-euglycemic clamp revealed similar whole-body insulin sensitivity and physical activity in the nonobese IUGR vs. CON, despite reduced heat production and energy expenditure. Compared with CON and IUGR, IPGR mimicking PNGR was lean and growth restricted with increased physical activity, O(2) consumption (VO(2)), energy intake, and expenditure. Although insulin sensitivity was no different in IPGR and PNGR, skeletal muscle insulin-induced glucose uptake was enhanced. This presentation proved protective against the chronologically earlier (5.5 months) development of obesity and dysregulated energy homeostasis after 19 wk on a postweaned high-fat diet. This protective role of PNGR on the metabolic IUGR phenotype needs future fine tuning aimed at minimizing unintended consequences.

IntroductionA lack of experience diagnosing and treating rare diseases contributes to delayed or incorrect diagnoses, and optimal clinical treatment is often unachievable. Miller-McKusick-Malvaux syndrome (3M syndrome, also known as dolichospondylic dysplasia) is a rare genetic disorder with unknown prevalence. It is inherited in an autosomal recessive manner and is characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features, and skeletal abnormalities.MethodsWhole exome sequencing (WES) was performed on the proband using Twist Human Core Exome Plus Kit (Twist Bioscience) and sequenced with Illumina technology (100x depth of mean coverage). Alignment and variant calling were performed with an in-house bioinformatics pipeline. The identified variants were annotated using the Ensembl VEP and multiple databases, including ClinVar, dbSNP, HGMD, and GnomAD. XHMMv1.0.ResultsThis article presents the diagnostic process in siblings diagnosed with 3M syndrome, caused by homozygous variant c.3523C > T (p.His1175Tyr) in the CUL7 gene.DiscussionThis is the first description of a familial syndrome from a local population. Identifying new gene variants has helped expand the spectrum of variations associated with the pathogenesis of 3M syndrome. The expanding database of genetic variants, combined with knowledge of the spectrum and severity of a patient’s clinical symptoms, provides the opportunity to identify genotype-phenotype correlation relevant to medical care.

Natural history of facial and skeletal features from neonatal period to adulthood in a 3M syndrome cohort with biallelic CUL7 or OBSL1 variants

3M syndrome is an autosomal recessive disorder characterized by severe growth retardation, distinct facial features, and skeletal changes, including long slender tubular bones and tall vertebral bodies. We report a Japanese patient with 3M syndrome caused by the biallelic novel variants c.1705_1708del and c.1989_1999del of CUL7. Skeletal features were consistent with 3M syndrome in the early neonatal period but became less obvious by 2 years of age.