The diagnostic utility of exome‐based carrier screening in families with a positive family history

Abstract

Identification of disease-causing variants in families with a history of a suspected recessive disorder is essential for appropriate counseling and reproductive decision making. The present case series depicts the utility of whole exome-based phenotypes-driven carrier analysis in 14 families with a positive family history. A phenotype-based analysis revealed a putative diagnostic yield of 71.4%. Proband sample, though insufficient, was available in only one family, which allowed the diagnosis to be confirmed. In the remaining nine families, despite the detection of heterozygous pathogenic/likely pathogenic variants, only a putative diagnosis was possible due to incomplete proband phenotyping as well as nonavailability of proband samples. We describe the youngest known patient homozygous for a likely pathogenic variant in PPP1R21. He is currently asymptomatic at 7 days of life and has a simplified gyral pattern on neuroimaging. The case series, though small, captures the challenges in the diagnosis of genetic disorders in low to middle income countries with in-equitable health care access. It reinforces the significance of detailed phenotyping in the proband as well as the importance of DNA storage for a conclusive diagnosis.A recurring post-test counseling challenge was risk ascertainment and reproductive decision making in subsequent pregnancies if the detected pathogenic/likely pathogenic variants are co-inherited, in families with a putative diagnosis. When opted for, prenatal testing in such a scenario would be limited in its ability to comment on the fetal status with respect to the disorder in the proband.

A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function

“…Over the last three years, homozygous variants in PPP1R21 have been described in 11 patients, most of them sharing developmental delay/intellectual disability, hypotonia, distinctive facial features, and brain anomalies [7]. In consistency with the previous reports [4][5][6][7][8], our patient showed a broad spectrum of clinical signs. He presented with respiratory distress shortly after birth (8/11), hypotonia (10/11), distinct developmental delay, and ID (9/11), including absent speech at the age of six.…”

“…Recent investigations describe a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss-of-function variants and imply a role for PPP1R21 within the endosomal sorting process or endosome maturation pathway [4]. So far, 11 individuals with homozygous pathogenic variants in the PPP1R21 gene have been linked to the neurological phenotype [4][5][6][7][8]. The phenotype of PPP1R21 cases shows a broad spectrum of abnormalities.…”

Expanding the phenotype of PPP1R21‐related neurodevelopmental disorder

“…Previous reports have only reported complete LoF variants (nonsense, frameshift, and splicing variants). [5][6][7][8][9] Here were report the first two subjects with PPP1R21 missense variant alleles and neurodevelopmental phenotype which along with the other novel variant expand the allelic spectrum of the disease. PPP1R21 has two domains, an N-terminus KLRAQ domain and a C-terminus TTKRSYEDQ domain.…”

“…Similar to our cohort, the prominence of the ventricular system has been noted in 8/11 (73%) previously published cases with available brain imaging. 3,5,6,[8][9][10] Delays in myelination was previously observed in 5/10 (50%) while abnormalities in the corpus callosum, as an indirect reflection of abnormal myelination, were more commonly observed in 8/11 (73%) of the previously published cases. 3,5,6,9,10 In contrast, the irregular outline of the bodies of the lateral ventricles was less frequently noted in only 4/11 (36%) of the published cases compared to our cohort.…”

“…6 Recently, four more individuals were reported, including one asymptomatic newborn diagnosed with exome-based carrier screening, making the total reported cases with PPP1R21-related NDD with hypotonia, facial dysmorphism, and brain abnormalities (OMIM #619383) to date 13 cases. [7][8][9][10] In this report, we present clinical, radiological, and molecular details of 11 previously unpublished individuals with PPP1R21related NDD from nine unrelated families with six novel variants in PPP1R21. The molecular diagnosis of PPP1R21-related NDD was made from clinical(cES) or research exome sequencing (rES).…”