Same performance of exome sequencing before and after fetal autopsy for congenital abnormalities: toward a paradigm shift in prenatal diagnosis?

Prenatal exome sequencing could be complex because of limited phenotypical data compared to postnatal/portmortem phenotype in fetuses affected by multiple congenital abnormalities (MCA). Here, we investigated limits of prenatal phenotype for ES interpretation thanks to a blindly reanalysis of postmortem ES data using prenatal data only in fetuses affected by MCA and harboring a (likely)pathogenic variant or a variant of unknown significance (VUS). Prenatal ES identified all causative variant previously reported by postmortem ES (22/24 (92%) and 2/24 (8%) using solo-ES and trio-ES respectively).

Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus.

During human organogenesis, lung development is a timely and tightly regulated developmental process under the control of a large number of signaling molecules. Understanding how genetic variants can disturb normal lung development causing different lung malformations is a major goal for dissecting molecular mechanisms during embryogenesis. Here, through exome sequencing (ES), array CGH, genome sequencing (GS) and Hi-C, we aimed at elucidating the molecular basis of bilateral isolated lung agenesis in three fetuses born to a non-consanguineous family.

Phenotypic and genetic spectrum of alveolar capillary dysplasia: a retrospective cohort study.

Objective: Alveolar capillary dysplasia (ACD) is one of the causes of pulmonary hypertension. Its diagnosis is histological but new pathogenetic data have emerged. The aim of this study was to describe a French cohort of patients with ACD to improve the comprehension and the diagnosis of this pathology which is probably underdiagnosed.

Novel SPEG Mutations in Congenital Myopathy without Centralized Nuclei.

Congenital myopathies are clinically and genetically heterogeneous, and are classified based on typical structural abnormalities on muscle sections. Recessive mutations in the striated muscle preferentially expressed protein kinase (SPEG) were recently reported in patients with centronuclear myopathy (CNM) associated in most cases with dilated cardiomyopathy. Here we report the identification of novel biallelic truncating SPEG mutations in a patient with moderate congenital myopathy without clinical and histological hallmarks of CNM and without cardiomyopathy.

Targeted Exome Sequencing Identifies as Involved in Monogenic Congenital Anomalies of the Kidney and Urinary Tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) occur in three to six of 1000 live births, represent about 20% of the prenatally detected anomalies, and constitute the main cause of CKD in children. These disorders are phenotypically and genetically heterogeneous. Monogenic causes of CAKUT in humans and mice have been identified.

Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes.

Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes.

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.

Background: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.

MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone.

Cilia have a unique diffusion barrier ("gate") within their proximal region, termed transition zone (TZ), that compartmentalises signalling proteins within the organelle. The TZ is known to harbour two functional modules/complexes (Meckel syndrome [MKS] and Nephronophthisis [NPHP]) defined by genetic interaction, interdependent protein localisation (hierarchy), and proteomic studies. However, the composition and molecular organisation of these modules and their links to human ciliary disease are not completely understood.

Musculoskeletal symptoms in patients with cryopyrin-associated periodic syndromes: a large database study.

Objective: To determine the type and frequency of musculoskeletal symptoms at onset and during followup of cryopyrin-associated periodic syndromes (CAPS).

Methods: We retrospectively recorded the articular and muscular symptoms of patients with CAPS followed up in French hospitals. Data were presented as frequencies or the median (range), and patient groups were compared using chi-square test, Fisher's exact test, and Mann-Whitney test.

Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita.

Arthrogryposis multiplex congenita is defined by the presence of contractures across two or more major joints and results from reduced or absent fetal movement. Here, we present three consanguineous families affected by lethal arthrogryposis multiplex congenita. By whole-exome or targeted exome sequencing, it was shown that the probands each harbored a different homozygous mutation (one missense, one nonsense, and one frameshift mutation) in GPR126.

A pure familial 6q15q21 split duplication associated with obesity and transmitted with partial reduction.

Familial transmission of chromosome 6 duplications is rare. We report on the first observation of a maternally-inherited pure segmental 6q duplication split into two segments, 6q15q16.3 and 6q16.

Fetal phenotype associated with the 22q11 deletion.

The 22q11 deletion syndrome is one of the most common human microdeletion syndromes, with a wide spectrum of abnormalities. The fetal phenotype associated with the 22q11 deletion is poorly described in the literature. A national retrospective study was performed from 74 feto-pathological examinations.

Delineation of EFTUD2 haploinsufficiency-related phenotypes through a series of 36 patients.

Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs.

Early-onset obesity and paternal 2pter deletion encompassing the ACP1, TMEM18, and MYT1L genes.

Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader-Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties.

Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases.

L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations.

Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature.

Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked multiple congenital abnormality/intellectual disability syndrome characterized by pre- and post-natal overgrowth, distinctive craniofacial features, macrocephaly, variable congenital malformations, organomegaly, increased risk of tumor and mild/moderate intellectual deficiency. In 1996, Glypican 3 (GPC3) was identified as the major gene causing SGBS but the mutation detection rate was only 28-70%, suggesting either genetic heterogeneity or that some patients could have alternative diagnoses. This was particularly suggested by some reports of atypical cases with more severe prognoses.

Severe prenatal renal anomalies associated with mutations in HNF1B or PAX2 genes.

Background And Objectives: Congenital anomalies of the kidney and urinary tract (CAKUT) are a frequent cause of renal failure in children, and their detection in utero is now common with fetal screening ultrasonography. The clinical course of CAKUT detected before birth is very heterogeneous and depends on the level of nephron reduction. The most severe forms cause life-threatening renal failure, leading to perinatal death or the need for very early renal replacement therapy.

Sirenomelia: a new type, showing VACTERL association with Thomas syndrome and a review of literature.

Sirenomelia or "mermaid syndrome" is a rare congenital anomaly known since antiquity. This congenital anomaly is defined as a polymalformative syndrome that associates major muscle and skeleton abnormalities (unique lower limbs) with visceral abnormalities (unilateral or bilateral renal agenesis, anomalies of the abdominal vascularisation). This phenotype, typical of sirenomelia syndrome, may be more or less severe.

KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome.

Goldberg-Shprintzen syndrome (GOSHS, MIM #609460) is an autosomal recessive disorder of intellectual disability, specific facial gestalt and Hirschsprung's disease (HSCR). In 2005, homozygosity mapping in a large consanguineous family identified KIAA1279 as the disease-causing gene. KIAA1279 encodes KIF-binding protein (KBP), whose function is incompletely understood.

EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia.

Background: Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations for which the molecular bases of syndromic forms are being identified at a rapid rate. In particular, the EFTUD2 gene encoding a protein of the spliceosome complex has been found mutated in patients with MFD and microcephaly (MIM610536). Until now, no syndrome featuring both MFD and OA has been clearly delineated.

The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients.

The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable '2q37-deletion syndrome' or Albright's hereditary osteodystrophy-like syndrome has been previously described.

Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion.

The SHANK3 protein is a scaffold protein known to stabilize metabotropic glutamate receptor mGluR5 in the post-synaptic membrane of neurons. It is associated with genetic vulnerability in autism and schizophrenia. Here we report the case of an 18 year-old male patient who displayed psychiatric features of bipolar affective disorder associated with early setting of dementia.