Rare genetic causes of primary microcephaly in two Saudi families identified via whole-exome sequencing: Genomic and phenotypic delineation of pathogenic CDK5RAP2 and CIT variants

Primary microcephaly-3 (MCPH3) and primary microcephaly-17 (MCPH17) are rare autosomal recessive disorders caused by biallelic variants in CDK5RAP2 and CIT , respectively. MCPH3 is characterized by microcephaly, neurodevelopmental delays, abnormal skin pigmentation, sensorineural hearing loss, and ophthalmological abnormalities. MCPH17 has more severe features, including progressive microcephaly, intellectual disability, spasticity, axial hypotonia, dysmorphic features, and cortical malformations. However, the clinical spectrum of MCPH3 and MCPH17, remains incompletely characterized. Here, we report two unrelated Saudi families with children diagnosed with primary microcephaly at birth. Whole-exome sequencing (WES) was performed on the index patients, and clinical data from affected siblings were collected to further delineate the conditions. In the first family, the patient had a homozygous CDK5RAP2 variant (MCPH3) and a tracheoesophageal fistula (TEF), a novel feature in this condition. The patient's older sibling, who also had MCPH3, showed notable height gain with growth hormone (GH), suggesting that GH may benefit patients with MCPH3. In the second family, a homozygous CIT variant (MCPH17) was associated with microcephaly, lissencephaly, neonatal seizures, and developmental delays. The patient had a deceased sibling with multiple congenital anomalies, demonstrating the intrafamilial variability of MCPH17. Overall, this study expands the clinical spectrum of MCPH3 and MCPH17; includes the first reported case of TEF in MCPH3; elucidates the ultra-rare clinical manifestation of neonatal seizures in MCPH17; and underscores the utility of WES in early diagnosis of genetically heterogeneous neurodevelopmental conditions. The findings can facilitate the necessary clinical management and counseling.