BackgroundProximal symphalangism is a rare disease with multiple phenotypes including reduced proximal interphalangeal joint space, symphalangism of the 4th and/or 5th finger, as well as hearing loss. At present, at least two types of proximal symphalangism have been identified in the clinic. One is proximal symphalangism-1A (SYM1A), which is caused by genetic variants in Noggin (NOG), another is proximal symphalangism-1B (SYM1B), which is resulted from Growth Differentiation Factor 5 (GDF5) mutations.Case presentationHere, we reported a Chinese family with symphalangism of the 4th and/or 5th finger and moderate deafness. The proband was a 13-year-old girl with normal intelligence but symphalangism of the 4th finger in the left hand and moderate deafness. Hearing testing and inner ear CT scan suggested that the proband suffered from structural deafness. Family history investigation found that her father (II-3) and grandmother (I-2) also suffered from hearing loss and symphalangism. Target sequencing identified a novel heterozygous NOG mutation, c.690C > G/p.C230W, which was the genetic lesion of the affected family. Bioinformatics analysis and public databases filtering further confirmed the pathogenicity of the novel mutation. Furthermore, we assisted the family to deliver a baby girl who did not carry the mutation by genetic counseling and prenatal diagnosis using amniotic fluid DNA sequencing.ConclusionIn this study, we identified a novel NOG mutation (c.690C > G/p.C230W) by target sequencing and helped the family to deliver a baby who did not carry the mutation. Our study expanded the spectrum of NOG mutations and contributed to genetic diagnosis and counseling of families with SYM1A.
Background Although Chromosomal microarray analysis (CMA) is a powerful diagnostic technology for detecting chromosomal copy number variants (CNVs), it detects numerous variants of unknown significance (VUSs), which poses a great challenge for genetic counselling. Terminal deletion of the long arm of chromosome 4 is a rare genetic aberration. Few cases of interstitial deletion sharing the common deleted segment have been reported. Case presentation A male foetus with a 7.22-Mb deletion at chromosome 4q32.2q32.3 was found in the proband. The paternal genotype was normal. His asymptomatic mother with a normal phenotype and intelligence was found to carry the same deletion at the long arm of chromosome 4. The clinical significance of arr[GRCh37] 4q32.2q32.3(162858958_170081268)×1 remains uncertain. To the best of our knowledge, this is the first case report on a VUS of 4q32 deletion and the second report of a heterochromatic CNV involving part of the long arm of chromosome 4 in a phenotypically normal mother and child. The identification of this case contributes to additional understanding of deletion at 4q32.2q32.3. This report may provide a reference for prenatal diagnosis and genetic counselling in patients who have genotypes of similar cytogenetic abnormalities. Conclusions The novel 7.22-Mb deletion at chromosome 4q32.2q32.3 (162858958-170081268) is a VUS. The foetus inherited this VUS from a phenotypically normal mother.
BackgroundWith the development of whole-genome sequencing, small chromosomal deletions and duplications could be found by NIPT. This study is to evaluate the clinical significance of fetal chromosomal karyotype analysis and chromosomal microarray analysis (CMA) to clarify the clinical significance of 528 cases of high-throughput sequencing noninvasive prenatal screening suggesting high-risk cases. MethodsNon-invasive prenatal screening showed that the fetus 21, 18, 13, sex chromosomes, and other chromosomes are at high risk of aneuploidy and fetal chromosome copy number variations (CNVs) are at high risk, requiring prenatal diagnosis Pregnant women are the research objects. After obtaining informed consent, fetal cells were obtained by amniocentesis or umbilical vein puncture for chromosomal karyotype and CMA analysis. All cases of childbirth were followed up by telephone over a period of 1 year.Results Among 528 fetuses, 447 were at high risk of aneuploidy. The positive predictive value (PPV) for trisomy 21(T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies (SCAs), and other chromosome aneuploidy was 85.24%, 51.52%, 12.5%, 50.82%, and 5.88% respectively. Another 81 cases of non-invasive prenatal screening suggest CNVs High risk. The PPV for CNVs was 34.57% .Among them, CNVs has a clear pathogenic significance can reach 24.69% . Follow-up of childbirth cases: Of the 62 pregnant women diagnosed with fetal SCA, 13 chose to continue their pregnancy, and the overall continued pregnancy rate was 20.97% (13/62); CNVs has no clear significance/no disease reported in 8 cases, 1 case After being lost to follow-up, all 7 cases chose to continue their pregnancy. One of the children was not informed about the specific situation; one girl had six fingers on both hands, and the rest had no abnormal growth; the remaining five children developed normally. ConclusionThis study has obtained relatively reliable PPV data for NIPT screening for chromosomal aneuploidy, which provides a reliable basis for clinical genetic counseling and treatment; it is recommended to perform prenatal diagnosis and perform chromosomal nucleus when non-invasive and high-risk prompts suspicious chromosomal abnormalities (over/under/microdeletion/microduplication). Type and CMA inspection, so that the inspection is more comprehensive and not easy to miss the diagnosis.
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