Founder effects of the homogentisate 1,2-dioxygenase (HGD) gene in a gypsy population and mutation spectrum in the gene among alkaptonuria patients from India

Clinical Rheumatology - Alkaptonuria (AKU) is a rare metabolic disease. The global incidence is 1:100,000 to 1:250,000. However, identification of a founder mutation in a gypsy population from...     

Goltz-Gorlin Syndrome: Revisiting the Clinical Spectrum

Objective

To describe the varying phenotypic spectrum of Focal Dermal Hypoplasia (FDH) and to emphasize the need for identifying the condition in mildly affected females which is crucial for offering a prenatal diagnosis in subsequent pregnancy owing to the risk of having a severely affected baby.

Methods

The phenotype-genotype correlation of 4 patients with FDH, over a period of 11 y from the genetic clinic in a tertiary care centre from Kerala, India was done.

Results

All four mutation proven patients were females (2 adults and 2 children). One of the adult female subjects were mildly affected, though she had a history of having a severely affected female child who expired on day six. Among the 2 affected children, one of them had an unaffected mother and the other had an affected mother.

Conclusions

FDH has a wide clinical spectrum from very subtle findings to severe manifestations. The lethality of the condition in males and the disfigurement and multisystem involvement in females highlights the importance of confirmation of diagnosis by molecular analysis so that the family can be offered prenatal diagnosis in subsequent pregnancy.

     

Recurrence of Angelman Syndrome in Siblings: Challenges in Genetic Counseling

The authors report a rare occurrence of two siblings with Angelman syndrome. Their karyotype revealed monosomy of chromosome 15 and a derivative chromosome 1 leading to Angelman syndrome. Their mother was a balanced translocation carrier involving chromosomes 1p and 15p. In her subsequent pregnancy, prenatal karyotype analysis was offered and the fetus was unaffected.     

Cardiac Spectrum,Cytogenetic Analysis and Thyroid Profile of 418 Children with Down Syndrome from South India: A Cross-sectional Study

Objective

To describe the spectrum of congenital heart disease in children with Down syndrome and their cytogenetic profile (and that of parents of those with translocation), and thyroid profile.

Methods

A cross sectional study was conducted in 418 consecutive patients with Down syndrome attending the Department of Pediatric Genetics from a tertiary care centre in Kerala with a comprehensive Pediatric Cardiac Program, from November 2005 through April 2012. All children were offered cytogenetic analysis and were subjected to echocardiography. Parental karyotyping was offered for children with translocation type of Down syndrome. The thyroid profiles of all children were checked at the first visit and once every 6 mo during follow up.

Results

Congenital heart disease was present in 256 (63.4 %) of 404 children with Down syndrome. Ventricular septal defect (72; 28.1 %) was the commonest, followed by atrio-ventricular septal defect (70; 27.3 %) and patent ductus arteriosus (43; 16.8 %). Surgical correction was accomplished in 104 (40.6 %) with excellent intermediate-term outcomes. Three hundred eighty seven of 418 children (92.6 %) underwent cytogenetic tests. The abnormalities included non-disjunction (340, 87.8 %), translocation (33, 8.5 %) and mosaicism (12, 3.1 %). Hypothyroidism was detected in 57 children (13.6 %).

Conclusions

The prevalence of congenital heart disease in children with Down syndrome in Kerala is the highest reported (63.4 %). Ventricular septal defect is the most common heart disease in the present study. The results highlight the changing attitudes of families towards the surgical correction of congenital heart disease in children with Down syndrome. Prevalence of hypothyroidism in Down syndrome in Kerala is 13.6 %.     

Elsahy–Waters syndrome is caused by biallelic mutations in CDH11

Elsahy–Waters syndrome (EWS), also known as branchial–skeletal–genital syndrome, is a distinct dysmorphology syndrome characterized by facial asymmetry, broad forehead, marked hypertelorism with proptosis, short and broad nose, midface hypoplasia, intellectual disability, and hypospadias. We have recently published a homozygous potential loss of function variant in CDH11 in a boy with a striking resemblance to EWS. More recently, another homozygous truncating variant in CDH11 was reported in two siblings with suspected EWS. Here, we describe in detail the clinical phenotype of the original CDH11‐related patient with EWS as well as a previously unreported EWS‐affected girl who was also found to have a novel homozygous truncating variant in CDH11, which confirms that EWS is caused by biallelic CDH11 loss of function mutations. Clinical features in the four CDH11 mutation‐positive individuals confirm the established core phenotype of EWS. Additionally, we identify upper eyelid coloboma as a new, though infrequent clinical feature. The pathomechanism underlying EWS remains unclear, although the limited phenotypic data on the Cdh11^?/? mouse suggest that this is a potentially helpful model to explore the craniofacial and brain development in EWS‐affected individuals.

     

Ptosis as a unique hallmark for autosomal recessive WNT1‐associated osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder, mainly characterized by bone fragility and low bone mass. Defects in the type I procollagen‐encoding genes account for the majority of OI, but increasingly more rare autosomal recessive (AR) forms are being identified, which are caused by defects in genes involved in collagen metabolism, bone mineralization, or osteoblast differentiation. Bi‐allelic mutations in WNT1 have been associated with a rare form of AR OI, characterized by severe osteoporosis, vertebral compression, scoliosis, fractures, short stature, and variable neurological problems. Heterozygous WNT1 mutations have been linked to autosomal dominant early‐onset osteoporosis. In this study, we describe the clinical and molecular findings in 10 new patients with AR WNT1‐related OI. Thorough revision of the clinical symptoms of these 10 novel patients and previously published AR WNT1 OI cases highlight ptosis as a unique hallmark in the diagnosis of this OI subtype.     

Novel biallelic variants expand the SLC5A6-related phenotypic spectrum

The sodium (Na⁺):multivitamin transporter (SMVT), encoded by SLC5A6, belongs to the sodium:solute symporter family and is required for the Na⁺-dependent uptake of biotin (vitamin B7), pantothenic acid (vitamin B5), the vitamin-like substance α-lipoic acid, and iodide. Compound heterozygous SLC5A6 variants have been reported in individuals with variable multisystemic disorder, including failure to thrive, developmental delay, seizures, cerebral palsy, brain atrophy, gastrointestinal problems, immunodeficiency, and/or osteopenia. We expand the phenotypic spectrum associated with biallelic SLC5A6 variants affecting function by reporting five individuals from three families with motor neuropathies. We identified the homozygous variant c.1285 A > G [p.(Ser429Gly)] in three affected siblings and a simplex patient and the maternally inherited c.280 C > T [p.(Arg94*)] variant and the paternally inherited c.485 A > G [p.(Tyr162Cys)] variant in the simplex patient of the third family. Both missense variants were predicted to affect function by in silico tools. 3D homology modeling of the human SMVT revealed 13 transmembrane helices (TMs) and Tyr162 and Ser429 to be located at the cytoplasmic facing region of TM4 and within TM11, respectively. The SLC5A6 missense variants p.(Tyr162Cys) and p.(Ser429Gly) did not affect plasma membrane localization of the ectopically expressed multivitamin transporter suggesting reduced but not abolished function, such as lower catalytic activity. Targeted therapeutic intervention yielded clinical improvement in four of the five patients. Early molecular diagnosis by exome sequencing is essential for timely replacement therapy in affected individuals.Subject terms: Peripheral neuropathies, Genetics research