Familial 3M Syndrome – as an Example of Diagnostic Difficulties in Rare Genetic Syndromes

A rare autosomal recessive genetic disorder, 3M syndrome, is characterized by severe intrauterine and postnatal growth retardation. Children with 3M syndrome typically exhibit short stature, facial deformities, long tubular bones, and high vertebral bodies but generally lack mental abnormalities or other organ damage. Pathogenic genes associated with 3M syndrome include CUL7, OBSL1 and CCDC8. The clinical and molecular characteristics of patient with 3M syndrome are unique and serve as important diagnostic indicators. In this case, the patient displayed square shoulders, scoliosis, long slender tubular bones, and normal neurological development. Notably, the patient did not exhibit the typical dysmorphic facial features, relative macrocephaly, or growth retardation commonly observed in individuals with 3M syndrome. Whole exon sequencing revealed a novel heterozygous c.56681+1G>C (Splice-3) variant and a previously reported nonsense heterozygous c.3341G>A (p.Trp1114Ter) variant of OBSL1. Therefore, it is important to note that the clinical features of 3M syndrome may not always be observable, and genetic confirmation is often required. Additionally, the identification of the c.5683+1G>C variant in OBSL1 is noteworthy because it has not been previously reported in public databases. Our study identified a new variant (c.5683+1G>C) of OBSL1 that contributes to expanding the molecular profile of 3M syndrome.

3M syndrome is an autosomal recessive disease characterized by severe pre-natal and post-natal growth retardation, dysmorphic facial features, and skeletal abnormalities. We present a patient with 3M syndrome caused by the compound heterozygous mutations p.Trp68* and p.Gly1452Asp in CUL7, the latter of which is novel, who exhibited a good body height response to growth hormone treatment. These results expand our knowledge of phenotype–genotype correlations in 3M syndrome, including correlations relevant to growth hormone response.

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.

Anaesthesia and orphan disease

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.

Background3M syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the cullin 7 (CUL7), obscurin-like 1 (OBSL1), and coiled-coil domain-containing protein 8 (CCDC8) genes and is characterized by pre- and postnatal growth retardation, short stature, dysmorphic facial features, and skeletal anomalies, with normal intelligence.Case presentationIn this study, we report a 6-year-old female patient from China diagnosed with 3M syndrome. The patient presented with typical clinical features of growth retardation and short stature, with normal intelligence. The patient’s dysmorphic facial features included relative macrocephaly, a protruding forehead, a triangular face, a pointed chin, a flat nasal bridge, full lips, a long philtrum, and a broad lower jaw. The skeletal survey was normal except for clinodactyly of the fifth fingers of both hands. Growth hormone (GH) deficiency was excluded by normal serum hormone levels and the GH stimulation test results. Whole-exome sequencing identified two heterozygous variants in CUL7, NM_014780.5: c.1639_1640del (p.Leu547Alafs*6), and NM_014780.5: c.4505T>C (p.Ile1502Thr). Parental Sanger sequencing confirmed these as compound heterozygous variants, with one variant inherited from each parent. Neither variant has been previously reported. The patient has been treated with recombinant human IGF-1 for 2 years since she was 4 years old and has achieved a growth velocity of approximately 6–7 cm per year.ConclusionsHerein, we describe a Chinese patient with 3M syndrome caused by novel biallelic pathogenic variants in CUL7 from a non-consanguineous family, expanding the genetic spectrum of CUL7 in the Chinese population.

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.

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.

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

3M syndrome is a rare autosomal recessive developmental disorder characterized by pre and postnatal growth deficiency, dysmorphic facial features, and normal intelligence. 3M syndrome should be suspected in a proband with a combination of characteristic or recognizable dysmorphic features. The diagnosis of 3M syndrome could be confirmed by identifying biallelic variants in CUL7, OBSL1, or CCDC8. Whole-exome sequencing (WES) was performed to identify genetic causes. Reverse-transcription polymerase chain reaction (RT-PCR) was performed to detect aberrant splicing events. Haplotypes were constructed using multiplex PCR and sequencing. Variants of the parental haplotype and target likely pathogenic variants were detected by PCR and Sanger sequencing from the embryos. Copy number variant (CNV) detection was performed by next-generation sequencing. We present the case of a nonconsanguineous Chinese couple with one abnormal pregnancy, where the fetus showed 3M phenotypes of shortened long bones. WES identified two novel heterozygous mutations in CUL7: NM_014780.5:c.354del (p.Gln119ArgfsTer52) and NM_014780.5:c.1373-15G>A. RT-PCR from RNA of the mother's peripheral blood leucocytes showed that c.1373-15G>A caused the insertion of a 13-bp extra intron sequence and encoded the mutant p.Leu459ProfsTer25. Both variants were classified as likely pathogenic according to ACMG/AMP guidelines and Clinical Genome Resource specifications. During genetic counseling, the options of prenatal diagnosis through chorionic villus sampling or amniocentesis, adoption, sperm donation, and electing not to reproduce, as well as preimplantation genetic testing for monogenic disorders (PGT-M), were discussed. The couple hopes to conceive a child of their own and refused to accept the 25% risk during the next pregnancy and opted for PGT-M. They finally successfully delivered a healthy baby through PGT-M. This study expanded the mutation spectrum of CUL7, detected the aberrant splicing event of CUL7 via RT-PCR, constructed the haplotype for PGT-M, and demonstrated the successful delivery of a healthy baby using PGT-M.

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.

Rapid advances in DNA sequencing technologies have made it increasingly cost-effective to obtain accurate and timely large-scale genomic sequence data on individuals (short read massively parallel or next generation [next-gen]). A next-gen molecular diagnostic approach that has seen rapid deployment in the clinic over the last year is exome sequencing. Whole exome sequencing covers all protein-coding genes in the genome (≈1.1% of genome), and an exome test for a single patient generates ≈6 gigabases (109 bp) of DNA sequence data. A key challenge facing routine use of next-gen data in patient diagnosis and management is data interpretation. What sequence variant findings are relevant to diagnosis (pathogenic mutations)? What sequence variant findings are relevant to clinical care but not necessarily to patient diagnosis (clinically actionable incidental data)? What sequence information should be stored, and where can it be stored? This review provides a tutorial on current approaches to answering these questions. A recent landmark study showed that application of next-gen sequencing to a large cohort of idiopathic dilated cardiomyopathy patients found ≈27% of patients to show mutations of the titin gene, the most complex gene in the genome (363 exons). We use titin in cardiomyopathy as an exemplar for explaining next-gen sequencing approaches and data interpretation. Decreasing sequencing costs and broad dissemination of next-generation (next-gen) equipment and expertise are increasing availability of massively parallel sequencing of patient DNA samples (short read massively parallel or next-gen sequencing).1,2 Most rapidly expanding is exome sequencing, where all protein-coding sequences (exons) are selected from total genomic DNA and selectively sequenced.3 Alternative approaches to next-gen sequencing include targeted sequencing (TS) and whole genome (complete genome) sequencing. Currently, marketed targeted Sanger sequencing panels using traditional individual exon-by-exon sequencing remain expensive and time consuming, and massively parallel next-gen approaches are beginning to supplant …

We report a case of segmental uniparental maternal hetero- and isodisomy involving the whole of chromosome 6 (mat-hUPD6 and mat-iUPD6) and a cullin 7 (CUL7) gene mutation in a Japanese patient with 3M syndrome. 3M syndrome is a rare autosomal recessive disorder characterized by severe pre- and postnatal growth retardation that was recently reported to involve mutations in the CUL7 or obscurin-like 1 (OBSL1) genes. We encountered a patient with severe growth retardation, an inverted triangular gloomy face, an inverted triangle-shaped head, slender long bones, inguinal hernia, hydrocele testis, mild ventricular enlargement, and mild mental retardation. Sequence analysis of the CUL7 gene of the patient revealed a homozygous missense mutation, c.2975G>C. Genotype analysis using a single nucleotide polymorphism array revealed two mat-hUPD and two mat-iUPD regions involving the whole of chromosome 6 and encompassing CUL7. 3M syndrome caused by complete paternal iUPD of chromosome 6 involving a CUL7 mutation has been reported, but there have been no reports describing 3M syndrome with maternal UPD of chromosome 6. Our results represent a combination of iUPDs and hUPDs from maternal chromosome 6 involving a CUL7 mutation causing 3M syndrome.

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.

Anaesthesia for emergency caesarean section in a woman with 3M syndrome