A Practical, Systematic Approach to Genetic Diagnosis in a Fetus or Neonate with Congenital Anomalies.

Congenital anomalies contribute significantly to perinatal, neonatal, and infant morbidity and mortality. The causes of these anomalies vary, ranging from teratogen exposure to genetic disorders. A high suspicion for a genetic condition is especially important because a genetic diagnosis carries a risk of recurrence in future pregnancies. Various methods are available for genetic testing, and each plays a role in establishing a genetic diagnosis. This review summarizes a practical, systematic approach to a fetus or neonate with congenital anomalies.

A novel pathogenic compound heterozygous variant in C12orf57 gene in a child with Temtamy syndrome presenting with overlapping phenotypic features of Kabuki-like syndrome.

BACKGROUND: Autism spectrum disorder is a major neurodevelopmental disorder. Temtamy syndrome is a rare syndromic intellectual developmental disorder that presents with global developmental delay, autism, seizures, and agenesis/dysgenesis of the corpus callosum. METHODS: We report a case of a male child who presented with global developmental delay, and autism. Additional clinical features in the child were prominent eyes, long palpebral fissures with eversion of lateral third of the lower eyelid, hypoplastic nipples, and persistent fetal fingertip pads. The clinical features were in favor of Kabuki-like syndrome. MRI brain revealed corpus callosal dysgenesis, mild cerebellar para-vermian, and vermian atrophy. RESULTS: Trio exome sequencing has revealed a novel pathogenic compound heterozygous variant c.145A >T (p.Lys49Ter) and c.224_242del (p.Val85GlufsTer88) in exon 2 of the C12orf57 gene. CONCLUSION: This is the first case of Temtamy syndrome reported from India with additional novel phenotypic features not reported previously and broadens the phenotypic spectrum of the disorder. In addition, it expands the spectrum of pathogenic variants in the C12orf57 gene.

Microcephalic primordial dwarfism with predominant Meier-Gorlin phenotype, ichthyosis, and multiple joint deformities-Further expansion of DONSON Cell Cycle-opathy phenotypic spectrum.

We report a patient with microcephalic primordial dwarfism with predominant Meier-Gorlin syndrome phenotype with ichthyosis and disabling multiple joint deformities in addition to classic features of the syndrome. The patient was a 10.5-year-old girl referred in view of short stature, joint deformities, and facial dysmorphism. There was history of intrauterine growth restriction and collodion like skin abnormality at birth. She had normal developmental milestones and intellect. On clinical evaluation, anthropometry was suggestive of proportionate short stature and microcephaly. There was abnormal posture due to spine and peripheral joint deformities, along with ichthyosis, facial, and digital dysmorphism. Skeletal radiographs showed radial subluxation, acetabular dysplasia and hip dislocation, bilateral knee joint dislocation, absent patellae, slender long bones with delayed bone age, and subluxation of small joints of hands and feet. Work up for metabolic bone disease and peripheral blood karyotype was normal. Whole exome sequencing revealed a pathogenic homozygous variant c.C1297T (p.Pro433Ser) in the exon 8 of DONSON gene. This report further expands the genotypic-phenotypic spectrum of the group of disorders known as Cell Cycle-opathies.

CEP135 associated primary microcephaly-A rare presentation in early second trimester.

Primary microcephaly (MCPH) is a rare neurogenic disorder with most cases being inherited in an autosomal recessive pattern. The present report is of a case of second gravid patient with recurrent fetal microcephaly with agenesis of corpus callosum, cerebellar hypoplasia and ventriculomegaly. Maternal TORCH profile and amniotic fluid chromosomal microarray were normal. Following the termination of pregnancy, the autopsy evaluation has shown additional findings of evolving craniosynostosis, and semilobar holoprosencephaly. Whole exome sequencing done on fetal DNA from amniotic fluid, revealed a pathogenic compound heterozygous variant (NM_025009.5) c.2863C>T (p.Arg955Ter) in exon 22 and c.1372_1375del (p.Lys459SerfsTer2) in exon 11 of CEP135 gene: known to cause primary microcephaly-8; and both partners in the couple are heterozygous carriers for the same. With the identification of MCPH genes and with the availability of next-generation sequencing (NGS) based exome sequencing, a definitive prenatal diagnosis of primary microcephaly and also appropriate genetic counselling for the couple has become possible.

Next-Generation Sequencing in a Cohort of Asian Indian Patients with the Duchenne Muscular Dystrophy Phenotype: Diagnostic Yield and Mutation Spectrum.

Multiplex ligation-dependent probe amplification (MLPA) detects exonic deletions and duplications in the DMD gene in around 65 to 70% of patients with the Duchenne muscular dystrophy (DMD) phenotype. This study looks at the diagnostic yield of next-generation sequencing (NGS) and the mutation spectrum in an Asian Indian cohort of MLPA-negative cases with the DMD phenotype. NGS-based sequencing of DMD gene was done in 28 MLPA-negative cases (25 male probands with the DMD phenotype and 3 obligate carrier mothers of deceased affected male patients) and disease-causing variants were identified in 19 (67.9%) of these cases. Further molecular testing in four of the remaining nine cases revealed gene variants associated with limb girdle muscular dystrophies. Thus, NGS-based multigene panel testing for muscular dystrophy-associated genes or clinical exome sequencing rather than targeted DMD gene sequencing appears to be a more cost-effective testing modality with better diagnostic yield, for MLPA-negative patients with the DMD phenotype.

An Infant with Blended Phenotype of Zellweger Spectrum Disorder and Congenital Muscular Dystrophy.

We report a newborn born to a consanguineous couple with antenatally detected dilatation of third ventricle, unilateral talipes, and intra uterine growth retardation. On examination, there was facial dysmorphism, hypotonia, encephalopathy, joint laxity and muscle hypertrophy in addition to left foot talipes. On evaluation, there were renal cortical cysts, rhizomelia, chondrodysplasia punctata and elevated muscle enzymes, along with a dilated third ventricle. As the phenotype was not consistent with any of the muscular dystrophies or the peroxisomal disorders, an exome sequencing was requested. It revealed a combination of Zellweger syndrome and Ullrich congenital muscular dystrophy type 1.

Alström Syndrome Presenting as Isolated Dilated Cardiomyopathy.

Cardiomyopathy is an etiologically heterogeneous condition, and non-syndromic as well as syndromic genetic causes are identified in a significant proportion of cases without a known acquired cause. The present report describes a 2-mo-old boy who presented initially with a referral diagnosis of isolated dilated cardiomyopathy, without any associated dysmorphism or malformations, and with history of similar cardiac disease and early infantile death in an elder male sibling. Next generation sequencing (NGS) based multigene panel testing of the cardiomyopathy-associated genes was done which revealed the diagnosis of Alström syndrome, based on which appropriate management and surveillance could be planned for the child and accurate genetic counseling could be provided to the parents. This report reiterates the fact that genetic testing for cardiomyopathy without an obvious acquired cause helps in identification of the underlying etiology, appropriate management, early diagnosis of syndromic forms, and monitoring and pre-symptomatic intervention for associated extracardiac complications.