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Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Differential diagnosis:Loeys-Dietz syndrome; probably the most similar condition, is characterised by generalised arterial tortuosity and aneurysms, cardiac defects and brain abnormalities; developmental delay can be present. Caused by mutations in the genes TGFBR1 and TGFBR2. Marfan syndrome (p. 534). Congenital contractural arachnodactyly, an autosomal dominant disorder caused by mutations in FBN2, does not show intellectual impairment or craniosynostosis. Homocystinuria caused by a deficiency of the enzyme cysthathionine synthetase, presents with a very similar phenotype and mental retardation but also subluxation of the lens and thrombophilia. Lujan–Fryns syndrome is an X-linked disorder also characterised by marfanoid habitus and mental delay but does not show craniosynostosis and joint contractures. Melnick-Needles syndrome (p. 130); frontometaphyseal dysplasia (p. 126).
Weaver Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Differential diagnoses for Weaver syndrome consist of several overgrowth syndromes that also produce tall stature, scoliosis, and variable intellect deficiency, including Sotos syndrome (downslanted palpebral fissures, prominent chin, malar flushing in children; mutation in NSD1), Malan syndrome (ophthalmologic abnormalities, normal growth in teenagers and young adults; mutation in NFIX), TBRS (round, heavy facial appearance with horizontal eyebrows and narrow palpebral fissures, increased weight, neuropsychiatric issues; mutation in DNMT3A), Beckwith−Wiedeman syndrome (macroglossia, earlobe creases/pits, omphalocele, visceromegaly, usually normal intellect, neonatal hypoglycemia, polyhydramnios; predisposition to embryonal tumors and Wilms tumor; abnormal regulation of gene transcription in two imprinted domains at the 11p15 growth regulatory region, including loss of methylation at imprinting center 2 on the maternal allele in 50% of cases, uniparental disomy for 11p15 in 20% of cases, gain of methylation at imprinting center 1 in 5% of cases; pathogenic variants within the maternal copy of CDKN1C in 5%–10% of sporadic cases and ≤40% of familial cases), Simpson−Golabi−Behmel syndrome type 1 (characteristic facial appearance, supernumerary nipples, polydactyly, diastasis recti, mutation in GPC3 and possibly GPC4), Marfan syndrome (usually normal cognitive abilities, myopia and lens dislocation, dilatation of the aorta, mitral and tricuspid valve prolapse, pectus abnormalities; mutation in FBN1), and congenital contractural arachnodactyly (or Beals syndrome; usually normal cognitive abilities, dilatation of the aorta, mitral and tricuspid valve prolapse, crumpled appearance to the top of the ear, pectus abnormalities; mutation in FBN2) [5].
The clinical application of single-sperm-based SNP haplotyping for PGD of osteogenesis imperfecta
Published in Systems Biology in Reproductive Medicine, 2019
Linjun Chen, Zhenyu Diao, Zhipeng Xu, Jianjun Zhou, Guijun Yan, Haixiang Sun
In the present study, OI resulted from heterozygous mutations (c.2299 G/A) in exon 33 of the COL1A1 gene. Direct mutation detection via sequencing is sufficient for the PGD of OI. However, OI is an autosomal dominant disorder, and ADO can cause misdiagnosis of dominant disorders during PGD (Wilton et al. 2009; Harper et al. 2012). Linkage analysis of polymorphic markers and mutated genes was used to establish a haplotype for identifying ADO and ensuring the accuracy of PGD. In a previous study, 9 of 10 blastocysts could not be diagnosed due to ADO when the gap–PCR method was used for the PGD of HbH disease, while the genotypes of all blastocysts were successfully diagnosed by NGS-based SNP haplotyping (Chen et al. 2017). Although ADO was also observed when NGS-based SNP haplotyping was used for the PGD of HbH disease, it did not affect the accuracy of PGD due to more informative SNPs used for establishing haplotypes. In addition, to avoid ADO, haplotyping can distinguish monosomy of chromosomes in embryos. Qubbaj et al. (2011) applied STR-based haplotyping for the PGD of congenital hyperinsulinism caused by a homozygous point mutation and identified one chromosome in an embryo harboring only the normally derived paternal allele; however, this embryo was diagnosed normally according to PCR-based sequencing. Here, haplotyping avoided misdiagnosis, which may have led to the transfer of an embryo with monosomy of that chromosome. Moreover, another advantage of haplotyping is the ability to identify meiotic recombination, which can impair the accuracy of PGD (Altarescu et al. 2008). We previously diagnosed congenital contractural arachnodactyly via NGS-based SNP haplotyping and observed homologous recombination of maternal origin, but this effect did not impair the accuracy of PGD due to the more informative SNPs used in this case (Chen et al. 2016). Therefore, haplotyping presents a number of advantages over the direct mutation detection by PCR, including the detection of ADO, chromosomal monosomy and recombination, to ensure the accuracy of clinical diagnosis.