Clinical Dysmorphology最新文献

Introduction: Agrin, encoded by AGRN, plays a vital role in the acetylcholine receptor clustering pathway, and any defects in this pathway are known to cause congenital myasthenic syndrome (CMS) 8 in early childhood with variable fatigable muscle weakness. The most severe or lethal form of CMS manifests as a fetal akinesia deformation sequence (FADS). To date, only one family has been reported with an association of null variants in AGRN and a lethal FADS.

Methods: We identified a nonconsanguineous couple with recurrent pregnancy loss. Detailed phenotyping of fetuses was performed via perinatal autopsy. Genetic evaluation was performed along with split-read analysis to identify variants.

Results: Perinatal phenotyping revealed an FADS in the family, and genomic testing identified novel null variants in AGRN. First, whole-exome sequencing revealed the maternally inherited heterozygous variant c.952+1_952+3del in AGRN in fetuses. Split-read analysis of the exome led to the identification of the paternally inherited second variant, a heterozygous deletion of 41.33 kb, encompassing exons 1 and 2 of AGRN.

Conclusion: This study highlights the importance of incorporating split-read analysis in clinical practice and emphasizes the association of null variants in AGRN with the FADS. To the best of our knowledge, this is the second report explaining FADS and null variants in AGRN.

Introduction: Kohlschütter-Tönz (KTS) is a rare autosomal recessive, genetically heterogeneous disorder characterized by a triad of early-onset seizures, global developmental delay or regression, and amelogenesis imperfecta of both temporary and permanent teeth. To date, 66 cases have been reported in the literature, of which 44 with genetic confirmation.

Case report: Here we report the observation of sibling pairs in a family from a small village in India who presented with nephrocalcinosis, distal renal tubular acidosis, and skeletal abnormality. Nephrocalcinosis has only been reported once before in an individual affected with KTS.

Results: Trio exome sequencing revealed a novel, homozygous, likely pathogenic variant, c.646-2_649del, in exon 9 of the ROGDI gene (NM_024589.3) in the first child. Sanger sequencing confirmed homozygosity in both children. Both parents are heterozygous carriers of the same variant.

Conclusion: Further research needs to be done to identify the exact mechanism by which ROGDI -encoded protein deficiency leads to nephrocalcinosis and distal renal tubular acidosis.

Introduction: Spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1) is an extremely rare skeletal dysplasia belonging to a group of disorders called linkeropathies. It is characterized by skeletal and connective tissue abnormalities. Biallelic variants in genes encoding enzymes that synthesize the tetrasaccharide linker region of glycosaminoglycans lead to linkeropathies, which exhibit clinical and phenotypic features that overlap with each other. SEMD-JL1 results in impaired growth and short stature, along with increased joint flexibility leading to limb joint dislocations and progressive spinal deformity.

Methods and result: Whole exome sequencing was performed on the patient's genomic DNA. A novel variant in the B3GALT6 gene was detected as homozygous. During the patient's follow-up, signs of cerebellar infarction was observed due to atlantoaxial subluxation. Posterior circulation ischemic strokes have not been described with SEMD-JL1 and it was the second case in the skeletal dysplasia group to develop posterior circulation ischemic stroke due to atlantoaxial luxation.

Conclusion: Linkeropathies present with varying clinical manifestations and necessitate comprehensive genetic testing for accurate diagnosis of this complex patient group. Skeletal dysplasias, such as spondyloepimetaphyseal dysplasia, may be accompanied by atlantoaxial instability that can lead to serious spinal symptoms and even sudden death.

Objective: This study aimed to elucidate the fetal ultrasound characteristics, pathology, and molecular genetic etiology of autosomal recessive tubular dysplasia.

Methods: This retrospective study examined four fetuses with autosomal recessive tubular dysplasia (ARRTD) from two pregnancies, utilizing ultrasound evaluations and fetal renal pathology. Whole-exome sequencing-copy number variation analysis was employed to identify gene mutations.

Results: We present for the first time renal vascular resistance in fetuses with ARRTD, characterized by increased renal blood flow resistance and reversed diastolic blood flow, indicating fetal renal insufficiency. This is the first report of a nonsense mutation (C.571C>T) found in the angiotensinogen gene.

Conclusion: ARRTD disease should be strongly suspected when ultrasound examinations reveal increased renal blood flow resistance, oligohydramnios, and inadequate bladder filling, regardless of the presence of renal abnormalities.

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome (MIM# 208250) is a rare monogenic disorder, characterized by early onset of camptodactyly, progressive coxa vara, bilateral arthropathy and constrictive pericarditis. The syndrome is caused by biallelic loss-of-function variants in PRG4 . Deficiency of PRG4 results in progressive worsening of joint deformity with age. Thirteen individuals with CACP syndrome from eight consanguineous Indian families were evaluated. We used exome sequencing to elucidate disease-causing variants in all the probands. These variants were further validated and segregated by Sanger sequencing, confirming the diagnosis of CACP syndrome in them. Seven females and six males aged 2-23 years were studied. Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13) [wrists (11/13), ankle (11/13), elbow (10/13) and knee (10/13)] were observed commonly. Five novel disease-causing variants (c.3636G>T, c.1935del, c.1134dup, c.1699del and c.962T>A) and two previously reported variants (c.1910_1911del and c.2816_2817del) were identified in homozygous state in PRG4 . We describe the phenotype and mutations in one of the large cohorts of patients with CACP syndrome, from India.