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09 May 2023: Articles  USA

Central Nervous System and Cardiac Abnormalities in the Setting of a De Novo Heterozygous Variant

Rare disease, Congenital defects / diseases, Rare coexistence of disease or pathology

Heerali Patel1ABDEF, Mohammed Elkhwad1ABCDE*, Gregory C. Martin1BCDE

DOI: 10.12659/AJCR.938651

Am J Case Rep 2023; 24:e938651




BACKGROUND: The Col4a1 gene encodes a portion of type IV collagen, a major component of the tissue basement membrane. Col4a1 mutations are rare, most frequently affect neonates, and occur at a de novo mutation rate between 27% and 40%. Mutations are commonly missense and pleiotropic, presenting with cerebrovascular, renal, ophthalmological, and muscular abnormalities, collectively known as Gould Syndrome. Cerebral small vessel disease is commonly associated with Gould Syndrome and Col4a1 mutations. Children can present with infantile hemiplegia/quadriplegia, stroke, epilepsy, motor dysfunction, or white matter changes of the eye.

CASE REPORT: A male infant at 38-week, 4-day gestation presented with microcephaly, scattered multifocal hemorrhagic/ischemic infarcts, ex-vacuo dilatation, polymicrogyria, ventricular septal defect, and narrowed aortic arch, seen on prenatal ultrasound and confirmed by fetal echocardiogram and fetal brain magnetic resonance imaging (MRI). Electroencephalogram showed frequent subclinical seizures that were difficult to control, requiring multiple agents. Ophthalmology evaluation demonstrated small, hypoplastic optic nerves of both eyes, concerning for septo-optic dysplasia. Postnatal brain MRI confirmed fetal findings. Postnatal genetic testing showed a de novo heterozygous variant of Col4a1 and 1 nonspecific contiguous region of copy neutral absence of heterozygosity on chromosome 11.

CONCLUSIONS: This neonate was prenatally diagnosed with central nervous system (CNS) abnormalities and postnatally found to have a de novo heterozygous Col4a1 variant. CNS, cardiac, renal, and hematological findings were likely associated with the Col4a1 mutation and, possibly, a recessive genetic disorder of chromosome 11. Col4a1 mutations are rare and have no definitive treatments. Subspecialist follow-up and supportive care are essential to reduce long-term complications.

Keywords: brain infarction, Porencephaly, Rare Diseases, Chromosome Aberrations, Basement Membrane, Genetic Pleiotropy, Prenatal Diagnosis, Magnetic Resonance Imaging, Loss of Heterozygosity, Child, Infant, Infant, Newborn, Pregnancy, Female, Humans, Male, Central Nervous System, Collagen Type IV, Stroke, Mutation


The Col4a1 gene codes for 2 pro-alpha1 chains of type IV collagen that constitute a major component of the tissue basement membrane. Mutations in the Col4a1 gene are inherited in an autosomal dominant pattern, commonly affecting neonates more than children or adults [1]. The de novo rate of Col4a1 mutations is between 27% and 40% [2,3]. Reported Col4a1 mutations are commonly missense variants of a glycine residue in the collagenous Gly-Xaa-Yaa helical domain of the COL4A1 protein [4,5]. Mutations are pleiotropic and present with a broad spectrum of abnormalities in the cerebrovascular, renal, ophthalmological, and muscular systems, collectively referred to as Gould Syndrome [6]. Phenotypic presentation associated with Col4a1 mutations and Gould Syndrome is variable [3,4]. One study cites tissue-specific mechanistic heterogeneity as a possible cause of variability, with integrin signaling affecting ocular and muscular variability more specifically [7].

Diagnoses associated with the Col4a1 mutation most commonly include hereditary porencephaly or parenchymal hemorrhage more broadly [3] and genetic cerebral small vessel disease [8], which affects the small arteries, capillaries, arterioles, and venules of the cerebrovascular system. In children, the Col4a1 mutation is associated with infantile hemiplegia or quadriplegia, stroke or epilepsy, motor dysfunction, and white matter changes of the eye on magnetic resonance imaging (MRI) [9].

Case Report

A male infant born at 38 weeks and 4 days gestation presented to the Neonatal Intensive Care Unit with microcephaly, central nervous system (CNS) anomalies, and a hypoplastic aortic arch. The mother was a 24-year-old, gravida 2 para 1, who received prenatal care. Prenatal ultrasound showed multiple fetal anomalies, including microcephaly, scattered multifocal hemorrhagic/ischemic infarcts, ex-vacuo dilatation, polymicrogyria, moderate ventricular septal defect (VSD), and a narrowed aortic arch. The mother subsequently underwent a fetal MRI of the brain, which confirmed suspected ultrasound findings. Fetal echocardiogram showed a dilated right cardiac chamber and mild hypoplasia of the left cardiac chambers, along with a moderate muscular VSD and narrow aortic arch. She was then seen by the Cardiology, Palliative Medicine, and Neonatology Departments for prenatal care.

The infant was born via cephalic vaginal delivery, with meconium-stained amniotic fluid. The birth weight was 2.45 kg. The APGAR scores at 1 and 5 min were 4 and 8, respectively. On physical examination, the infant had a dusky appearance of the bilateral feet and cool extremities. No other physical abnormalities were seen. The baby was limp at birth with no spontaneous respiratory effort, required positive pressure ventilation at birth, and was then transitioned to continuous positive airway pressure. Postnatal echocardiography showed a fenestrated atrial septum and moderate mid-muscular VSD, mild to moderate hypoplastic left ventricle, moderately hypo-plastic left aortic arch, small to moderate patent ductus arteriosus, and suprasystemic right ventricular systolic pressure. The infant was started on intravenous (i.v.) prostaglandin E1 owing to suspected coarctation of the aorta. He was then given i.v. epinephrine and dopamine drips because of hypotension. Respiratory support was escalated from nasal continuous positive airway pressure to noninvasive positive pressure ventilation as a result of apnea, presumably secondary to prostaglandin administration. An echocardiogram obtained after initiation of prostaglandin E demonstrated a widely patent aortic arch with a VSD. A subsequent echocardiogram showed no evidence of coarctation, and prostaglandin E was discontinued.

Electroencephalogram showed frequent subclinical seizures. Seizures were difficult to control, requiring multiple agents, including i.v. levetiracetam 75 to 150 mg, i.v. lacosamide 6 mg every 12 h, and i.v. phenobarbital 13 to 50 mg. A subsequent electroencephalogram after treatment showed no additional seizures. An ophthalmology evaluation showed small, hypo-plastic optic nerves of both eyes, concerning for septo-optic dysplasia. The left eye showed a posterior polar cataract with microspherophakia. Postnatal MRI of the brain (Figures 1, 2) confirmed findings of multifocal infarcts of unknown etiology, diffuse mild polymicrogyria, dysgenesis of the corpus callosum, optic nerve hypoplasia, a defect within the intraventricular septum, and inferior vermian hypoplasia.

Genetic analysis with rapid whole exome sequencing and chromosomal microarray were obtained owing to concern for parental consanguinity. XomeDxXpress Clinical Exome Sequence Analysis showed a de novo heterozygous variant at c. 2771 G>A of the Col4a1 gene. Chromosomal microarray analysis revealed a normal male sex chromosome with no other clinically significant abnormalities and a nonspecific contiguous region of copy neutral absence of heterozygosity on chromosome 11.

Postnatal renal ultrasound showed mild calyceal dilatation of the left kidney. Cytomegalovirus workup was negative.

The infant was weaned to room air and continued to improve on oral feeds. By the time of discharge, the infant was taking most of the feeds orally. The infant was discharged on room air and oral hydrochlorothiazide-spironolactone 3 mg, given the VSD with the pulmonary over-circulation. Oral phenobarbital 20 mg/5 mL, oral levetiracetam 100 mg/mL, and oral lacosamide 10 mg/mL were continued for seizure management with the Neurology Department.


Col4a1 mutations constitute a wide range of phenotypic presentations that are categorized under Gould Syndrome, including cerebral small vessel disease, which has histopathologic findings including reduced vessel lumens and wall thickening that cause reduced perfusion [8]. Common manifestations of the Col4a1 variants include leukoaraisosis, strokes, and perinatal intracerebral hemorrhage with consequent porencephaly, all of which constitute the “COL4A1 stroke syndrome” [2]. Cerebral small vessel disease is commonly associated with ischemic strokes in 20% to 30% of cases [8]. Hereditary angiopathy with nephropathy, aneurysms, and muscle vessel involvement are associated with asymptomatic cerebral small vessel disease, large vessel cerebral involvement, and systemic involvement (eg, kidney, muscle, and eye) in the setting of Col4a1 mutations [10]. Diagnosis is determined by the various clinical findings, along with genetic testing for the Col4a1 variant.

No specific treatment is available for the sequelae of Col4a1 genetic variants. Stroke risk reduction, especially in the presence of hypertension, and neuroprotection are important to reduce the risk of intracerebral hemorrhage or other CNS complications [2]. Additional supportive care and follow-up with subspecialists for systemic involvement are necessary to prevent progression. Counseling to avoid risk factors such as smoking, anticoagulants, and potentials for head trauma should be provided [11]. Other individualized needs regarding home care and minimizing emotional, physical, and financial burden on caregivers are important to consider.

Genetic counseling is needed to identify the mechanism of inheritance and potential downstream effects on family members and descendants. Prenatal testing is a consideration when the familial pathogenic variant is known [11].

Lastly, previous cases of Col4a1 variants are consistent with the neurological presentation in this case, including cerebral small vessel disease and optic nerve defects, broadly categorized under Gould Syndrome. Another study identified a single nucleotide polymorphism in the Col4a1 gene associated with arterial stiffness [12]. The cardiac findings in our patient, namely aortic coarctation and VSD, have not previously been associated with Gould Syndrome or a Col4a1 variant and potentially convey the presence of multiple disorders. One possible causative factor for an additional disorder in this patient is the nonspecific contiguous region of copy neutral absence of heterozygosity on chromosome 11. The presence of this region in both parents may be indicative of a recessive disorder caused by a gene within the absence of heterozygosity region.


This case presents a neonatal patient who was prenatally diagnosed with CNS and cardiac abnormalities and postnatally found to have a de novo heterozygous variant of the Col4a1 gene and a nonspecific contiguous region on chromosome 11. Postnatal CNS, cardiac, renal, and hematological findings constituted a likely association with the Col4a1 genetic mutation, alongside a possible recessive genetic disorder originating on chromosome 11. Differential diagnoses included infectious causes, such as congenital cytomegalovirus. Col4a1 mutations are rare and have no definitive treatments, owing to the variability in presentation. Follow-up subspecialist care based on specific organ systems affected and supportive care for the patient and family, especially in the pediatric field, are essential to reduce long-term complications.


1.. Vahedi K, Alamowitch S, Clinical spectrum of type IV collagen (COL4A1) mutations: A novel genetic multisystem disease: Curr Opin Neurol, 2011; 24(1); 63-68

2.. Volonghi I, Pezzini A, del Zotto E: Curr Med Chem, 2010; 17(13); 1317-24

3.. Meuwissen MEC, Halley DJJ, Smit LS: Genet Med, 2015; 17(11); 843-53

4.. Kuo DS, Labelle-Dumais C, Gould DB: Hum Mol Genet, 2012; 21(R1); R97-110

5.. Yoneda Y, Haginoya K, Arai H: Am J Hum Genet, 2012; 90(1); 86-90

6.. Boyce D, McGee S, Shank L: Epilepsy Behav, 2021; 125; 108365

7.. Mao M, Popli T, Jeanne M: Dis Model Mech, 2021; 14(4) dmm048231

8.. Litak J, Mazurek M, Kulesza B, Cerebral small vessel disease: Int J Mol Sci, 2020; 21(24); 9721

9.. Shah S, Ellard S, Kneen R: Dev Med Child Neurol, 2012; 54(6); 569-74

10.. Plaisier E, Gribouval O, Alamowitch S: N Engl J Med, 2007; 357(26); 2687-95

11.. Plaisier E, Ronco P, Adam NP: GeneReviews®, 1993, Seattle (WA), University of Washington, Seattle

12.. Tarasov KV, Sanna S, Scuteri A: Circ Cardiovasc Genet, 2009; 2(2); 151-58

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American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923