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Their loss is our gain: regressive evolution in vertebrates provides genomic models for uncovering human disease loci

16 Aug, 17 | by hqqu

What can an armadillo tell us about blindness and an anteater about dental disorders? Many animals have evolved traits that are similar to human genetic diseases, although for these animals the traits are adaptive, not disease-causing. Intriguingly, when animals possess these disease-mimicking traits, they frequently have disabling mutations in the same genes underlying the human genetic disorders. Here we show how medical geneticists can leverage the genomes of these disease-mimicking animals, which range from blue whales to sloths and pangolins to naked mole-rats, to corroborate and discover novel gene-disease associations for diseases related to vision, teeth and other organs. (By Dr. Christopher A Emerling, http://jmg.bmj.com/content/early/2017/08/16/jmedgenet-2017-104837 )

Mutations in SCAPER cause autosomal recessive retinitis pigmentosa with intellectual disability

9 Aug, 17 | by hqqu

Retinitis pigmentosa (RP) is a hereditary eye disease marked by progressive degeneration of the retina – the part of the eye that is home to the photosensitive cells. RP can occur by itself or in combination with other impairments. The latter cases are known as syndromic RP. We identified mutations in a gene named SCAPER in four patients from Israel and Spain, affected by RP and intellectual disability. This gene was not previously associated with a human disease. Our findings place SCAPER as a gene necessary for normal function of both the retina and the brain. (By Dr. Tamar Ben-Yosef, http://jmg.bmj.com/content/early/2017/08/09/jmedgenet-2017-104632 )

SCAPER expression pattern in the mouse retina. (A) Sagittal sections of adult mouse retina were immunostained with an anti-SCAPER antibody (red); (B) DAPI nuclear staining (blue); (C) merge of images A and B. SCAPER expression was observed in the retinal pigment epithelium (RPE), in photoreceptor outer segments (OS) and inner segments, including the outer nuclear layer (ONL), in the inner plexiform layer (IPL) and in the ganglion cell layer (GCL). OS, outer segments; INL, inner nuclear layer. Scale bar, 20µm.

Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability

9 Aug, 17 | by hqqu

Hyperphenylalaninemia is one of the most common inherited metabolic diseases diagnosed in the newborn screening and until now follow-up investigation included differential diagnosis of phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficiency. With the description of patients with biallelic variants in co-chaperone DNAJC12 (van Spronsen et al 2017), the paradigm of hyperphenylalaninemia needs reconsideration. DNAJC12-deficient patients may present initially without any symptoms, with only mild attention deficit or with a severe intellectual disability, and need immediate and appropriate treatment (BH4, l-dopa/Carbidopa and 5-hydroxytryptophan). Thus, every newborn with hyperphenylalaninemia, in which PKU and BH4 deficiency were excluded need to be tested for DNAJC12 variants. (By Prof. Dr. Beat Thöny, http://jmg.bmj.com/content/early/2017/08/09/jmedgenet-2017-104875 )

A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

5 Aug, 17 | by hqqu

Two mutated copies of the SLC26A4 gene are associated with Pendred syndrome, comprised of bilateral hearing loss with enlargement of the vestibular aqueduct (EVA) and thyroid goiter.  Other EVA patients have a normal thyroid gland and only one mutated copy of SLC26A4.  Our study identified the same combination, or haplotype, of noncoding sequence variants upstream of the non-mutated copy of SLC26A4 in most of these nonsydromic EVA patients.  This haplotype defines the most common allele associated with hereditary hearing loss in Caucasians.  Testing for this haplotype will facilitate the genetic and prognostic counseling of many patients with EVA. (By Dr. Andrew J Griffith, http://jmg.bmj.com/content/early/2017/08/05/jmedgenet-2017-104721 )

(Source: https://www.nidcd.nih.gov/health/enlarged-vestibular-aqueducts-and-childhood-hearing-loss )

Increased Breast Cancer Risk in MSH2 Carriers from a Large Canadian Familial Cancer Registry

4 Aug, 17 | by hqqu

Lynch Syndrome is an inherited condition involving several well-characterized mutations; MLH1, MSH2, MSH6, and PMS2. Affected families are counselled on their increased risk of numerous malignant diagnoses including colorectal cancer and endometrial cancer, as well as central nervous system malignancies and several other gastrointestinal and genitourinary cancers. Management of Lynch Syndrome includes prevention and surveillance, such as colonoscopies for early detection of colorectal cancer, and prophylactic hysterectomy for endometrial cancer.

There is a suggestion that Lynch Syndrome may confer an increased risk of breast cancer, however the literature remains conflicting. Our work identified an increased risk in MSH2 carrier women in a large Canadian registry (SIR 3.11 (95%CI: 1.95-4.71), lifetime cumulative incidence 22%). Furthermore, we have demonstrated the high penetrance of Lynch Syndrome cancers within their individual family pedigrees, and that similar to other Lynch Syndrome diagnoses, breast cancers occur at a younger age compared to the unaffected Canadian population. Ours is the first study to demonstrate an association between breast cancer risk and family history of Lynch Syndrome-related malignancies, and reports on a large number of breast cancer events compared to many published series.

Identification of breast cancer as a Lynch Syndrome related malignancy could have significant implications for mutation carriers. Effective surveillance and prevention strategies are available and could be further explored. These interventions have proven beneficial in other high-risk populations, such as BRCA1/2 carriers. (By Dr. Mira Goldberg, http://jmg.bmj.com/content/early/2017/08/04/jmedgenet-2017-104542 )

Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders

28 Jul, 17 | by hqqu

Mitochondrial cytopathies are genetic diseases, some of which result from mutations affecting part of the multiple DNA molecules located within mitochondria (mtDNA). Coexistence of mutant and wild-type mtDNA molecules is called “heteroplasmy” and defines a “mutant load”. Disease symptoms occur when the mutant load surpasses a tissue-specific threshold.

Owing to the absence of therapy and the high recurrence risk for these serious diseases, at-risk couples commonly request a prenatal diagnosis, based on determination of the mutant load on a single chorionic villous sample (CVS). We have shown that this mutant load is widely heterogeneous within placentas, so that mutant load determined from CVS should be interpreted with caution and associated to/substituted by a mutant load measurement on amniocytes. (By Drs. Julie Steffann and Jean-Paul Bonnefont, http://jmg.bmj.com/content/early/2017/07/27/jmedgenet-2017-104615 )

A germline deletion of 9p21.3 presenting as familial melanoma, astrocytoma and breast cancer: clinical and genetic counselling challenges

28 Jul, 17 | by hqqu

Very few families with 9p21.3 deletion have been described. These families are at risk of developing melanoma and nerve sheath tumors.  We report a family with several members affected by melanoma, astrocytoma, neurofibromas, and breast cancer. They have a 9p21.3 deletion containing 9 genes. While mutations within individual genes are associated with distinct hereditary cancer syndromes, we do not know what kinds of tumors can occur when several genes are missing. This complex case illustrates the need for healthcare providers trained in genetics to be involved in hereditary cancer testing, which is becoming increasingly utilized in various clinical settings. (by Dr. Jaime Vengoechea and Christine Tallo, MMSc, CGC, http://jmg.bmj.com/content/early/2017/07/27/jmedgenet-2017-104690 )

Identification of the first dominant mutation of LAMA5 gene causing a complex multisystem syndrome due to dysfunction of the extracellular matrix

22 Jul, 17 | by hqqu

Laminin alpha 5 gene (LAMA5) plays a master role in the extracellular matrix in all mammalian tissues; mice defective of LAMA5 do not overcome embryonic life. In this paper a previously unknown autosomal dominant clinico-pathological syndrome is described which segregates with the mutation c.9418G>A (p.V3140M) of LAMA5 in an informative Italian family.  The results of this study highlight the importance of LAMA5 in the histogenesis, developmental patterning, maintenance and repair of all body tissues and also open new perspectives to investigate on the pathogenesis of pathologies  such as, night blindness, intestinal malabsorption, osteoarthritis, altered scarring, and  new strategies for their treatment. (By Dr. Teresa Esposito, http://jmg.bmj.com/content/early/2017/07/22/jmedgenet-2017-104555 )

Assessing genome-wide copy number variation in the Han Chinese population

13 Jul, 17 | by hqqu

Copy number variation (CNV) is an important source of human genetic diversity, which contributes to Mendelian disorders as well as complex diseases. We conducted a genome-wide CNV discovery in 451 males of Han Chinese by using high-density comparative hybridization arrays. The CNVs we reported are in high quality and representative of Han Chinese from 28 dialects and diverse geographical regions. More than half of the variants are novel and have not been reported yet. These data are complementary to public sources of human genomic data, and the CNV map may facilitate in the identification of pathogenic CNVs and further biomedical studies involving the Han Chinese populations. (By Prof. Dr. Shuhua Xu, http://jmg.bmj.com/content/early/2017/07/13/jmedgenet-2017-104613 )

The focal facial dermal dysplasias: phenotypic spectrum and molecular genetic heterogeneity

29 Jun, 17 | by hqqu

Focal Facial Dermal Dysplasias (FFDDs) are four developmental genetic disorders with similar bilateral “scar-like” facial lesions at birth and are classified by the lesion location: bitemporal for the FFDD subtypes 1-3 and peri-auricular for FFDD subtype 4. This review summarizes the clinical features of the subtypes and the genetic defects underlying FFDD3 and FFDD4, while the underlying genetic defects in FFDD1 and FFDD2 remain unknown. Additionally, two autosomal dominant developmental disorders with overlapping facial lesions, Ablepharon-Macrostomia syndrome and Barber-Say syndrome, are discussed. Recognition of these disorders and further investigation of their genetic defects may provide insights into the genetic pathways of facial development. (By Brenden Chen, http://jmg.bmj.com/content/early/2017/06/29/jmedgenet-2017-104561 )

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