PMC9465251_01
Phenotype and gene variation in TRIO cases. (A) Delayed development of cerebellar (equivalent to 20 weeks) of case 1 in 25 weeks of pregnancy was detected by prenatal ultrasound. (B)
TRIO c.3506delG variation in case 1 and case 2 were confirmed by Sanger sequencing. (C) Family pedigree of TRIO variation cases. (D) Schematic representation of TRIO domains and LOF variations identified in affected individuals (blue: macrocephaly; green: microcephaly; red: variant found by us).
fneur-13-948877-g0001.jpg
PMC9465251_03_fneur-13-948877-g0001.jpg
F1
SEC14 domain, several spectrin repeats, two Rho-guanine exchange factor units (GEFD1 and GEFD2), and a C-terminal serine/threonine kinase domain (Figure 1D). Spectrin repeats domain was known to bind different TRIO regulators to inhibit TRIO-mediated RAC1 activation. LOF variants in TRIO was less well-defined. LOF variants in group 3 were shown in Figure 1D. Remarkably, LOF variants were distributed along the TRIO sequence with most cases presenting microcephaly but two carrying c.77C>A (p.Ser26*) and c.7050del (p.Val2351Cysfs*62) variant with macrocephaly, respectively (Figure 1D, Table 2).
PMC9465251_02
Phenotype and gene variation in CNKSR2 cases. (A,B) A severe hydrocephalus, and a widened bilateral ventricle (2.5 cm) and third ventricle (1 cm) were scanned by MRI. (C)
CNKSR2 c.1282C>T variation in CNKSR2 family was confirmed by Sanger sequencing. (D) Family pedigree of CNKSR2 cases. (E) Non-sense variants, splice site mutations, and small insertions/deletions reported in literature (brick red and blue) and this report (red). Hotspot 1: the upstream region of N-terminal PDZ domain; Hotspot 2: the downstream region of C-terminal PH domain; Hotspot 3: PH domain.
fneur-13-948877-g0002.jpg
PMC9465251_03_fneur-13-948877-g0002.jpg
F2
Approximately, 2 years later, this family was admitted to our hospital with the complaint of the widening lateral ventricle of the second pregnancy at 24 weeks (1.00 cm) by prenatal ultrasound (Supplementary Figure 2). Sanger sequencing confirmed the c.1282C>T variant in this second child (Figure 2C). Interestingly, all variants were considered as LOF, such as genomic deletions, non-sense variants, splice site mutations, and small insertions or deletions (Figure 2E) (red: non-sense variant found in this report). Remarkably, LOF variants were distributed along the TRIO sequence with most cases presenting microcephaly but two carrying c.77C>A (p.Ser26*) and c.7050del (p.Val2351Cysfs*62) variant with macrocephaly, respectively (Figure 1D, Table 2). PDZ domain (hotspot 1), the downstream region of the C-terminal PH domain (hotspot 2) and the PH domain (hotspot 3, blue) (Figure 2E). Phenotypic differences such as the onset age of seizures, severity of language impairment, and ADHD were not significant between hotspot 1 and 2.
PMC9465251_03
Phenotype and gene variation in TRIO cases. (A) Delayed development of cerebellar (equivalent to 20 weeks) of case 1 in 25 weeks of pregnancy was detected by prenatal ultrasound. (B)
TRIO c.3506delG variation in case 1 and case 2 were confirmed by Sanger sequencing. (C) Family pedigree of TRIO variation cases. (D) Schematic representation of TRIO domains and LOF variations identified in affected individuals (blue: macrocephaly; green: microcephaly; red: variant found by us).
fneur-13-948877-g0001.jpg
PMC9465251_03_fneur-13-948877-g0001.jpg
F1
SEC14 domain, several spectrin repeats, two Rho-guanine exchange factor units (GEFD1 and GEFD2), and a C-terminal serine/threonine kinase domain (Figure 1D). Spectrin repeats domain was known to bind different TRIO regulators to inhibit TRIO-mediated RAC1 activation. LOF variants in TRIO was less well-defined. LOF variants in group 3 were shown in Figure 1D. Remarkably, LOF variants were distributed along the TRIO sequence with most cases presenting microcephaly but two carrying c.77C>A (p.Ser26*) and c.7050del (p.Val2351Cysfs*62) variant with macrocephaly, respectively (Figure 1D, Table 2).
Phenotype and gene variation in CNKSR2 cases. (A,B) A severe hydrocephalus, and a widened bilateral ventricle (2.5 cm) and third ventricle (1 cm) were scanned by MRI. (C)
CNKSR2 c.1282C>T variation in CNKSR2 family was confirmed by Sanger sequencing. (D) Family pedigree of CNKSR2 cases. (E) Non-sense variants, splice site mutations, and small insertions/deletions reported in literature (brick red and blue) and this report (red). Hotspot 1: the upstream region of N-terminal PDZ domain; Hotspot 2: the downstream region of C-terminal PH domain; Hotspot 3: PH domain.
fneur-13-948877-g0002.jpg
PMC9465251_03_fneur-13-948877-g0002.jpg
F2
Approximately, 2 years later, this family was admitted to our hospital with the complaint of the widening lateral ventricle of the second pregnancy at 24 weeks (1.00 cm) by prenatal ultrasound (Supplementary Figure 2). Sanger sequencing confirmed the c.1282C>T variant in this second child (Figure 2C). Interestingly, all variants were considered as LOF, such as genomic deletions, non-sense variants, splice site mutations, and small insertions or deletions (Figure 2E) (red: non-sense variant found in this report). Remarkably, LOF variants were distributed along the TRIO sequence with most cases presenting microcephaly but two carrying c.77C>A (p.Ser26*) and c.7050del (p.Val2351Cysfs*62) variant with macrocephaly, respectively (Figure 1D, Table 2). PDZ domain (hotspot 1), the downstream region of the C-terminal PH domain (hotspot 2) and the PH domain (hotspot 3, blue) (Figure 2E). Phenotypic differences such as the onset age of seizures, severity of language impairment, and ADHD were not significant between hotspot 1 and 2.