Long-read DNA sequencing fully characterized chromothripsis in a patient with Langer-Giedion syndrome and Cornelia de Lange syndrome-4.

Chromothripsis is a type of chaotic complex genomic rearrangement caused by a single event of chromosomal shattering and repair processes. Chromothripsis is known to cause rare congenital diseases when it occurs in germline cells, however, current genome analysis technologies have difficulty in detecting and deciphering chromothripsis. It is possible that this type of complex rearrangement may be overlooked in rare-disease patients whose genetic diagnosis is unsolved. We applied long read nanopore sequencing and our recently developed analysis pipeline dnarrange to a patient who has a reciprocal chromosomal translocation t(8;18)(q22;q21) as a result of chromothripsis between the two chromosomes, and fully characterize the complex rearrangements at the translocation site. The patient genome was evidently shattered into 19 fragments, and rejoined into derivative chromosomes in a random order and orientation. The reconstructed patient genome indicates loss of five genomic regions, which all overlap with microarray-detected copy number losses. We found that two disease-related genes RAD21 and EXT1 were lost by chromothripsis. These two genes could fully explain the disease phenotype with facial dysmorphisms and bone abnormality, which is likely a contiguous gene syndrome, Cornelia de Lange syndrome type IV (CdLs-4) and atypical Langer-Giedion syndrome (LGS), also known as trichorhinophalangeal syndrome type II (TRPSII). This provides evidence that our approach based on long read sequencing can fully characterize chromothripsis in a patient's genome, which is important for understanding the phenotype of disease caused by complex genomic rearrangement.

Skeletal abnormalities of tricho-rhino-phalangeal syndrome type I.

The tricho-rhino-phalangeal syndrome (TRPS) type I is a rare genetic disorder related to the TRPS1 gene mutation in chromosome 8, characterized by craniofacial abnormalities and disturbances in formation and maturation of bone matrix. The hallmarks are sparse and brittle hair, tendency to premature baldness, bulbous nose called pear-shaped, long and flat filter and low ear implantation. The most noticeable skeletal changes are clinodactyly, phalangeal epiphyses of the hands appearing as cone-shaped, short stature and hip joint malformations. We report a case of a teenager boy diagnosed with TRPS and referred for rheumatologic evaluation due to joint complaints.

Syndrome disintegration: Exome sequencing reveals that Fitzsimmons syndrome is a co-occurrence of multiple events.

In 1987 Fitzsimmons and Guilbert described identical male twins with progressive spastic paraplegia, brachydactyly with cone shaped epiphyses, short stature, dysarthria, and "low-normal" intelligence. In subsequent years, four other patients, including one set of female identical twins, a single female child, and a single male individual were described with the same features, and the eponym Fitzsimmons syndrome was adopted (OMIM #270710). We performed exome analysis of the patient described in 2009, and one of the original twins from 1987, the only patients available from the literature. No single genetic etiology exists that explains Fitzsimmons syndrome; however, multiple different genetic causes were identified. Specifically, the twins described by Fitzsimmons had heterozygous mutations in the SACS gene, the gene responsible for autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS), as well as a heterozygous mutation in the TRPS1, the gene responsible in Trichorhinophalangeal syndrome type 1 (TRPS1 type 1) which includes brachydactyly as a feature. A TBL1XR1 mutation was identified in the patient described in 2009 as contributing to his cognitive impairment and autistic features with no genetic cause identified for his spasticity or brachydactyly. The findings show that these individuals have multiple different etiologies giving rise to a similar phenotype, and that "Fitzsimmons syndrome" is in fact not one single syndrome. Over time, we anticipate that continued careful phenotyping with concomitant genome-wide analysis will continue to identify the causes of many rare syndromes, but it will also highlight that previously delineated clinical entities are, in fact, not syndromes at all. © 2016 Wiley Periodicals, Inc.

Anormalidades esqueléticas da síndrome tricorrinofalangiana tipo I / Skeletal abnormalities of tricho-rhino-phalangeal syndrome type I

Resumo A síndrome tricorrinofalangiana (STRF) tipo I é uma doença genética rara, relacionada com a mutação no gene TRPS1 do cromossomo 8. É caracterizada por anomalias craniofaciais e distúrbios na formação e maturação da matriz óssea. As características são cabelos ralos e quebradiços, tendência à calvície prematura, nariz bulboso em formato de pera, filtro nasal longo e plano e baixa implantação das orelhas. As alterações esqueléticas mais notáveis são a clinodactilia, as epífises das falanges das mãos em forma de cone, a baixa estatura e as malformações na articulação do quadril. Relata-se o caso de um adolescente diagnosticado com STRF e encaminhado para avaliação reumatológica em decorrência de queixas articulares.

Abstract The tricho-rhino-phalangeal syndrome (TRPS) type I is a rare genetic disorder related to the TRPS1 gene mutation in chromosome 8, characterized by craniofacial abnormalities and disturbances in formation and maturation of bone matrix. The hallmarks are sparse and brittle hair, tendency to premature baldness, bulbous nose called pear-shaped, long and flat filter and low ear implantation. The most noticeable skeletal changes are clinodactyly, phalangeal epiphyses of the hands appearing as cone-shaped, short stature and hip joint malformations. We report a case of a teenager boy diagnosed with TRPS and referred for rheumatologic evaluation due to joint complaints.

Tricho-rhino-phalangeal syndrome type 1 as an outcome of in vitro fertilization?

Trichorhinophalangeal syndrome type I [OMIM #190350] is an autosomal dominant disorder. Common features are: Slowly growing sparse hair, laterally thin eyebrows, bulbous tip of the nose, long philtrum, thin upper lip, protruding ears. Common skeletal anomalies include shortening of phalanges and metacarpals causing mild to severe brachydactyly, cone shaped epiphyses, hip dysplasia and short stature. Recently many reports have been published on the use of assisted reproductive technology (ART) and the increased risk of congenital major malformations or syndromes. We present a 6 years old Turkish Trichorhinophalangeal syndrome (TRPS) case of a twin pair after in vitro fertilization (IVF). TRPS with IVF pregnancy has not been reported previously. This new case reported herein will contribute to a better understanding whether ART pregnancy increases congenital malformations.

Pronounced short stature in a girl with tricho-rhino-phalangeal syndrome II (TRPS II, Langer-Giedion syndrome) and growth hormone deficiency.

We report on a 10-year-old girl with tricho-rhino-phalangeal syndrome type II (TRPS II) and pronounced short stature (-4.8 SD). The patient has an interstitial chromosome 8q24.1 deletion of 12-15 Mb. The deletion spans all genes from CSMD3 to at least ANXA13 including the TRPS1 and EXT1 genes, which are responsible for the TRPS II phenotype. In addition to the features of TRPS II, the patient had growth hormone (GH) deficiency with diminished response in three stimulation tests. Therapy with 0.2 mg GH/kg/week led to an increase of growth velocity from 2.5 to 6.6 cm/year. To our knowledge, such a combination of TRPS II and GH deficiency has not yet been described.

Missense mutation of TRPS1 in a family of tricho-rhino-phalangeal syndrome type III.

We report a new Japanese family with tricho-rhino-phalangeal syndrome type III (TRPS III) who have a missense mutation (Arg908Gln) of theTRPS1 gene (TRPS1) in affected individuals of the family. This study supports the notion that TRPS III results from missense mutations in exon 6 of TRPS1.

Mapping of the bone morphogenetic protein 1 gene (BMP1) to 8p21: removal of BMP1 from candidacy for the bone disorder in Langer-Giedion syndrome.

Fifteen cosmids containing sequences from the human bone morphogenetic protein 1 gene (BMP1) were isolated from a cosmid library. The probe was a 483-bp DNA obtained by the reverse transcriptase-PCR method using primers designed according to the reported BMP1 sequence. When the positive cosmids were tested for chromosome fluorescence in situ hybridization, all showed signals at 8p21. The results indicated that BMP1 is not responsible for Langer-Giedion syndrome, whose putative gene has been assigned to 8q24.